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Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression
Open accessAbstract
Neuronal activation induces rapid transcription of immediate early genes (IEGs) and longer-term chromatin remodeling around secondary response genes (SRGs). Here, we use high-resolution chromosome-conformation-capture carbon-copy sequencing (5C-seq) to elucidate the extent to which long-range chromatin loops are altered during short- and long-term changes in neural activity. We find that more than 10% of loops surrounding select IEGs, SRGs, and synaptic genes are induced de novo during cortical neuron activation. IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20 min after stimulation, prior to peak messenger RNA levels. By contrast, the SRG Bdnf engages in both pre-existing and activity-inducible loops that form within 1-6 h. We also show that common single-nucleotide variants that are associated with autism and schizophrenia are colocalized with distinct classes of activity-dependent, looped enhancers. Our data link architectural complexity to transcriptional kinetics and reveal the rapid timescale by which higher-order chromatin architecture reconfigures during neuronal stimulation.
Overview
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Written from the paper’s full text.
TL;DR
Using 5C-seq across activity states and time points in mouse cortical neurons, this study shows that neuronal activation rapidly reconfigures long-range chromatin loops around immediate early genes and slower secondary response genes. It links de novo versus pre-existing loop classes to distinct transcriptional kinetics and to schizophrenia- or autism-associated noncoding variants.
Key findings
- Within 12.2 Mb queried around *Arc*, *Bdnf*, *Fos*, *Nrxn1*, *Syt1*, and *Nlgn3*, the authors detected 215 activity-invariant, 29 activity-induced, and 9 activity-decommissioned loops; more than 10% of loops surrounding select IEGs, SRGs, and synaptic genes were induced de novo.
- Activity-induced loops anchored by activity-induced enhancers (class 1, n = 11) connected to genes with a 24-fold activity-dependent expression increase, whereas pre-existing loops anchored by activity-induced enhancers (class 2, n = 41) connected to genes with a 1.3-fold increase.
- *Fos* and *Arc* formed singular short-range loops with activity-dependent enhancers that peaked by 20 min after stimulation, before peak mRNA at 60 min; *Bdnf* engaged in longer class 1 loops of 840 kb and 1,700 kb and class 2 loops that formed at 60–360 min, with maximum signal at 360 min.
- Schizophrenia-associated noncoding SNVs (n = 80, P < 5 × 10−8) preferentially colocalized with class 3 loops anchored by activity-decommissioned enhancers, while autism-associated SNVs (n = 126, P < 10−4) colocalized with class 2 loops anchored by activity-inducible enhancers.
Methods
- Primary murine cortical neurons were cultured for 15 days in vitro and treated for 24 h with 10 μM bicuculline, 1 μM tetrodotoxin, or left untreated; acute time-course experiments used 24 h TTX followed by 0, 5, 20, 60, or 360 min of bicuculline.
- The authors generated high-resolution 5C-seq maps across 12.2 Mb around selected genes, plus H3K27ac ChIP–seq, total RNA-seq, and reanalyzed published mouse and human Hi-C data; loops were called with 3DeFDR and Hi-C loop-calling methods, and enhancer–gene links were modeled with an adapted activity-by-contact approach.
- Disease-variant analyses used GWAS summary statistics for schizophrenia and autism spectrum disorders, SNP matching, Fisher’s exact tests, and LD score regression.
Limitations
- The paper states that future functional dissection with genome editing is required to test whether disease-associated variants disrupt enhancers or loop structure, and that genome-wide Hi-C under diverse activity-induction conditions is needed to estimate class effects more precisely.
- The paper notes that published Hi-C data represent only the untreated activity state, so activity-induced class 1 loops could not be assessed genome-wide; it also calls for future human activity-dependent loop maps.
- Evident from the text: the main architectural findings come from an in vitro mouse cortical neuron system and 5C maps limited to 12.2 Mb around selected loci, and the disease-variant results are colocalization/enrichment analyses rather than causal tests.
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78 Own result · 19 Not checked yet · 19 Own interpretation · 15 Own method · 3 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Activity-invariant loops anchored by activity-decommissioned enhancers showed a strong and unchanged interaction frequency (class 3, Fig. 3f).”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20 min after stimulation, prior to peak messenger RNA levels.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“whereas the total sum interaction frequency made by each gene showed no correlation with gene expression”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Class 2 pre-existing loops connect genes involved in several general cellular functions such as RNA processing to activity-induced enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“as well as a consistent increase in H3K27ac signal at enhancers that connected through these loops to activity-upregulated genes”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“although class 1 loops are a rare occurrence, they corresponded to a 24-fold increase in activity-induced expression”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Comparatively more genes engaged in class 2 loops but on average displayed a modest 1.3-fold increase in expression in active neurons”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“class 3 pre-existing loops anchored by activity-decommissioned enhancers connect genes linked to synaptic organization and the regulation of synaptic activity”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Pre-existing class 2 and class 3 loops are markedly more abundant in number than class 1 loops.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“activity-invariant loops pre-wired in inactive neurons and anchored by activity-induced enhancers (n = 41) (class 2)”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelationaln = 41- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We noticed a strong correlation between activity-dependent changes in promoter H3K27ac signal and gene expression”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We first stratified H3K27ac peaks into activity-invariant (n = 14,424), activity-induced (n = 6014), and activity-decommissioned (n = 5402) putative enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
hedged- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activity-induced and activity-decommissioned loops showed two- to threefold upregulations or downregulations of interaction frequency, respectively”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > 3D genome maps of dynamic loops during cortical neuron inhibition and activation.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“genes connected to activity-induced enhancers via activity-invariant loops (Class 2) displayed a modest but significant upregulation in expression after neuronal activation when we queried genome-wide loops”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelationaln = 4,764- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
In the paper
“whereas maximum Bdnf upregulation occurred after 6 h”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
What the sources say
- Not checked yetcites [9] Tyssowski, K. M. et al. Different neuronal activity patterns induce different gene expression programs. Neuron 98, 530–546 e511 (2018). source
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We find that more than 10% of loops surrounding select IEGs, SRGs, and synaptic genes are induced de novo during cortical neuron activation.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we observed a strong increase in interaction strength at the most strongly activity-upregulated genes”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We also show that common single-nucleotide variants that are associated with autism and schizophrenia are colocalized with distinct classes of activity-dependent, looped enhancers.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activity-induced loops anchored by activity-induced enhancers (class 1) underwent a 2.2-fold change in interaction frequency after 24 h of Bic treatment”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“We found that the cohort of genes undergoing decreased expression in class 3 loops were predominantly involved in synapse organization and signaling, including Gria1”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our third, ‘long-range enhancer’ model markedly increased the variance of activity-dependent expression explained”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By contrast, the SRG Bdnf engages in both pre-existing and activity-inducible loops that form within 1–6 h.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“we re-analyzed a recently published RNA-seq time course during pharmacological neuronal activation9 and found maximum activation of the IEGs Fos and Arc by 60 min”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
What the sources say
- Not checked yetcites [9] Tyssowski, K. M. et al. Different neuronal activity patterns induce different gene expression programs. Neuron 98, 530–546 e511 (2018). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Fos was upregulated more than 100-fold”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Class 1 loops connect Fos, Bdnf, and Tmed10 to activity-inducible enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activity-induced loops anchored by activity-induced enhancers (n = 11) (class 1)”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelationaln = 11- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20 min after stimulation, prior to peak messenger RNA levels.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20 min after stimulation, prior to peak messenger RNA levels.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By contrast, the SRG Bdnf engages in both pre-existing and activity-inducible loops that form within 1–6 h.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“We applied published methods17 to identify 24,937 loops in cortical neurons”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
What the sources say
- Not checked yetcites [33] Bonev, B. et al. Multiscale 3D genome rewiring during mouse neural development. Cell 171, 557–572 e524 (2017). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“By adding the covariate of the H3K27ac signal at the nearest enhancer, we only marginally increased the performance of the model”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“but were still lower in overall looping strength than the activity-invariant contacts”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > 3D genome maps of dynamic loops during cortical neuron inhibition and activation.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“activity-invariant loops pre-wired in inactive neurons and anchored by activity-decommissioned enhancers that lose their H3K27ac signal upon chronic neuronal activation (n = 15) (class 3)”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaindirectn = 15- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Promoter H3K27ac alone explained 51.7% of the variance in gene expression after neuronal activation in our 5C regions”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“models that used loop strength (Fig. 2i) or the ABC value (loop strength × enhancer H3K27ac) between the selected enhancer and promoter (Fig. 2j) as covariates correlated similarly well with gene expression changes”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“genes looped to activity-decommissioned enhancers via activity-invariant loops (class 3) genome-wide exhibited a slight reduction in expression after neural activation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaindirectn = 3,259- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“interaction strength further strengthens after neuronal stimulation in the case of activity-invariant loops pre-wired to activity-induced enhancers (class 2, Fig. 3f)”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we unexpectedly observed that IEGs connect to enhancers via singular short-range loops that occur de novo after activation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“connected into a complex network of multiple long-distance class 1 and class 2 loops”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By contrast, when class 3 loops overlap schizophrenia- or ASD-associated SNVs, we observe that their target genes are preferentially downregulated by activity”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
In the paper
“We found that noncoding SNVs associated with schizophrenia38 (n = 80, P < 5 × 10−8, see Supplementary Methods) preferentially colocalize with class 3 loops anchored by activity-decommissioned enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
What the sources say
- Not checked yetcites [38] Schizophrenia Working Group of the Psychiatric Genomics Consortium Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source
plaincorrelationaln = 80- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed striking differences in loop and enhancer induction kinetics for IEGs and SRGs in our 5C regions.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“whereas ASD-associated SNVs (n = 126, P < 10−4, see Supplementary Methods) colocalize with class 2 loops anchored by activity-inducible enhancers39”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
What the sources say
- Not checked yetcites [39] Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol. Autism 8, 21 (2017). source
plaincorrelationaln = 126- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Bdnf class 1 loops did not interact until 60 (Figs. 4h and 5e,g, ‘Enhancer 1’) or 360 minutes (Figs. 4g and 5f,h, ‘Enhancer 2’) after stimulation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Differential IEG and SRG looping kinetics after an acute neural activation time course.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“at least two class 2 activity-invariant loops anchored by activity-induced enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SRG Bdnf was upregulated 30-fold after neuronal activation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we demonstrate that activity-inducible enhancers engage in either de novo (class 1) or pre-existing (class 2) loops”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“observed that the enhancer–promoter loop strength for IEGs peaks before maximum mRNA levels occur (60 min after stimulation)”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Differential IEG and SRG looping kinetics after an acute neural activation time course.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Arc was upregulated more than 12-fold after neural activation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We note that Fos engages in different short-range loops after 5 min, 20 min, and 24 h of neural activation, shifting interaction strength from a nearby enhancer to one that is more distal”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“We identified 24,544 unique loops from published Hi-C data created in human brain tissue derived from the germinal zone and cortical plate41”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
What the sources say
- Not checked yetcites [41] Won, H. et al. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538, 523–527 (2016). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For example, enhancers and loops surrounding Fos and Arc peak in signal strength roughly 20 min after the induction of neuronal activity, before peak mRNA levels.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we identify a unique set of loops that are anchored by enhancers that decrease in activity during chronic stimulation.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We lifted-over our activity-dependent enhancer classes to the human genome and classified 4,098 class 2 and 3,822 class 3 loops from human brain tissue”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we found that rapid response IEGs form significantly fewer loops (Fig. 4k), shorter loops (Fig. 4l), and connect to a lower number of activity-induced putative enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we found that rapid response IEGs form significantly fewer loops (Fig. 4k), shorter loops (Fig. 4l), and connect to a lower number of activity-induced putative enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that the class 1 loops surrounding Fos and Arc achieved peak contact frequency as quickly as 20 min after initiating stimulation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Differential IEG and SRG looping kinetics after an acute neural activation time course.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“at early time points Fos interacted with an additional enhancer (Fig. 5a, ‘Enhancer 2’) compared to its loop induced by 24 h of activity (Fig. 4d, ‘Enhancer 1’)”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Differential IEG and SRG looping kinetics after an acute neural activation time course.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In cases in which class 2 loops overlap schizophrenia- or ASD-associated SNVs, we observe that they connect activity-inducible enhancers to target genes that are preferentially upregulated after neural activation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“whereas SRGs connect to multiple activity-inducible enhancers via a complex network of invariant and de novo loops.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Loops connected by Bdnf were significantly longer than those connected by Fos and Arc”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we found that rapid response IEGs form significantly fewer loops (Fig. 4k), shorter loops (Fig. 4l), and connect to a lower number of activity-induced putative enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“One such gene is Slc4a10 (ref. 45), which loops downstream to a schizophrenia-associated SNV (Extended Data Fig. 10f) that overlaps a region of activity-decommissioned H3K27ac”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
What the sources say
- Not checked yetcites [45] Sinning, A., Liebmann, L. & Hubner, C. A. Disruption of Slc4a10 augments neuronal excitability and modulates synaptic short-term plasticity. Front. Cell. Neurosci. 9, 223 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“also connected in a singular loop with an activity-induced enhancer”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By contrast, Bdnf loops and enhancers gain strength in parallel with mRNA levels over a longer time of sustained stimulation (360 min).”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we identified only a single 40-kb-sized class 1 loop with an activity-induced enhancer”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By contrast, ASD-associated SNVs preferentially colocalize with class 2 loops that connect activity-inducible enhancers to activity-upregulated target genes.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Activity-induced loops are not present earlier in cortical neuron differentiation.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“5C data correlateions cluster by condition.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
plaincorrelationaln = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Genes found in the ‘regulation of trans-synaptic signaling’ and ‘synapse organization’ GO terms enriched in activity downregulated class 3 genes.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, owing to the extremely high on-diagonal counts we found this approach often overestimated the expected background at short-range interactions (less than 100 kb).”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Hi-C loop calling.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Foxp1 and Slc4a10 fall opposite disease-associated variants in conserved classified loops.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
plaincorrelationaln = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Often, promoters formed several loops, interacting with multiple enhancers.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Linear regression modeling.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data link architectural complexity to transcriptional kinetics and reveal the rapid timescale by which higher-order chromatin architecture reconfigures during neuronal stimulation.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We confirmed high reproducibility of loops across four 5C replicates taken across two independent batches of neuronal cultures”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > 3D genome maps of dynamic loops during cortical neuron inhibition and activation.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“We confirmed that an enhancer–promoter loop that has been reported previously as activity-dependent at Fos via 3C-PCR (ref. 36) was classified here as an activity-induced loop”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > 3D genome maps of dynamic loops during cortical neuron inhibition and activation.
What the sources say
- Not checked yetcites [36] Joo, J. Y., Schaukowitch, K., Farbiak, L., Kilaru, G. & Kim, T. K. Stimulus-specific combinatorial functionality of neuronal c-fos enhancers. Nat. Neurosci. 19, 75–83 (2016). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results reveal a potential mechanistic role for class 3 loops and activity-decommissioned enhancers in facilitating homeostatic plasticity during chronic high neural activity.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our data reveal that the genes connected to activity-induced enhancers via rare de novo loops show the largest effect size in activity-dependent expression”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data indicate that long-range enhancers and loop strength can provide significant improvement in the prediction of activity-dependent expression compared to proximal, nearby enhancers.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Activity-dependent levels of gene expression are predicted by looping and enhancer acetylation.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our observation that class 1 activity-induced enhancers and loops connect rapidly to IEGs before mRNA levels peak supports the assertion that the two are functionally linked”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Differential IEG and SRG looping kinetics after an acute neural activation time course.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“the colocalization of schizophrenia-associated SNVs with class 3 loops suggests that defects in enhancer decommissioning might contribute to synaptic plasticity defects in neuropsychiatric diseases47.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
What the sources say
- Not checked yetcites [47] Luscher, C. & Malenka, R. C. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb. Perspect. Biol. 4, a005710 (2012). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our data show that pre-wired and de novo loops that are anchored by activity-inducible enhancers connect to target genes that exhibit activity-dependent upregulation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that neuronal activity results in dynamic changes in the 3D genome that may inform precise temporal control of activity-dependent gene expression over short and long time scales.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Conversely, invariant loops that are anchored by activity-decommissioned enhancers connect to genes that are downregulated after neuronal activity”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data reveal that specific common SNVs associated with neuropsychiatric diseases colocalize with loops that connect distinct activity-dependent enhancer classes to unique target genes.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results are striking as they suggest that some disease-specific neuronal phenotypes may arise from noncoding SNVs that have different effects depending on the class of loops that they anchor”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our 5C and genome-wide Hi-C results support our working model in which poised or pre-existing loops that connect to target genes in advance of activity-induced enhancer activation are abundant but have a modest effect on gene expression.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We find that H3K27ac signal at distal looped enhancers is a notably better predictor of activity-dependent target gene expression than nearest enhancers.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data suggest that enhancer–target gene prediction would be facilitated by the use of chromatin architecture maps, instead of relying on the enhancer that is closest on the linear genome.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Background loops were confirmed to display the same loop distances and loop sizes as the real loop set.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Disease-associated GWAS SNV enrichment.
plain- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Activity-induced and activity-invariant loops are reproducible across condition replicates.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
plainn = 4- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“5C is subject to specific biases, such as primer GC content resulting in annealing or PCR biases, that methods such as Hi-C are not.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > 5C interaction analysis.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interaction scores have proven to be informatively comparable across replicates and conditions21”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > 5C interaction analysis.
What the sources say
- Not checked yetcites [21] Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281–1295 (2013). source
boosted- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Verification of the eRNA signature captures enhancer activity dynamics.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Such an extreme enrichment of single primer–primer pairs does not resemble the broader distribution of elevated counts, spanning clusters of neighboring primer–primer pairs, that exists at bona fide looping interactions across 5C and Hi-C data.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > 5C interaction analysis.
plain- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Through this approach we achieved an eFDR of 6.6% for Bic-only (activity-induced) loops using a difference threshold of 6.75, a significance threshold of −10 × log2(0.08) (that is, a P value of 0.08 resulting from the logistic fit to the observed over expected data), and a cluster size threshold of 5.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Quantitative 5C loop identification.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 24
- Probably not a substantial claim. 21
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The majority of differentially expressed genes in class 2 versus class 3 loops were upregulated and downregulated, respectively, due to activity”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“stratify them into class 2 (n = 4,764) and class 3 (n = 3,259) groups”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
plainn = 4,764- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IEGs in our 5C regions form simple short-range loops with activity-dependent enhancers, and thus fall nearly exclusively in the class 1 category”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“resulting in the sensitive detection of 215 activity-invariant, 29 activity-induced, and 9 activity-decommissioned loops within the 12.2 Mb of the genome queried”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > 3D genome maps of dynamic loops during cortical neuron inhibition and activation.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we find that specific genes that are involved in homeostatic plasticity, such as Gria1, are connected in class 3 loops to activity-decommissioned enhancers and are downregulated during chronic high activity.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Our LD score regression analysis confirmed a stronger enrichment of ASD-associated heritability in class 2 loop anchors than that for class 3, whereas heritability for schizophrenia displayed the opposite trend”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
What the sources say
- Not checked yetcites [43] Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Bdnf enhancers and expression were upregulated in parallel with loops and did not reach maximum signal in our time course until 360 min of stimulated activity”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Differential IEG and SRG looping kinetics after an acute neural activation time course.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We also observe that schizophrenia-associated SNVs are enriched at class 3 loops and are connected to downregulated genes after synaptic activity.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“at least two class 1 activity-induced loops anchored by activity-induced enhancers, but spanning longer distances (840 kb and 1,700 kb) than those formed with IEGs”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The loops formed by Bdnf preferentially targeted its first promoter, from which we observed the highest level of transcription and strongest upregulation after 24 h of Bic-induced neuronal activation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Foxp1, which has been found previously to regulate brain development and synaptic plasticity44, displays remarkable mouse–human conservation of local genome architecture, and loops to several ASD-associated SNVs (Extended Data Fig. 10c) and activity-induced enhancers”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
What the sources say
- Not checked yetcites [44] Araujo, D. J. et al. Foxp1 in forebrain pyramidal neurons controls gene expression required for spatial learning and synaptic plasticity. J. Neurosci. 37, 10917–10931 (2017). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The enhancers that loop to both Fos and Arc peak in activity 20 min after neuronal activity, and exhibit lower activity at all other time points”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Differential IEG and SRG looping kinetics after an acute neural activation time course.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Class 1 and class 2 loops connect to genes exhibiting a 24- and 1.3-fold activity-dependent increase in expression, respectively.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, 25,722 ‘background loops’ were identified as those Hi-C contact matrix entries that had a P value of >0.99 and an interaction frequency count of >0 in both cortical plate and germinal zone data sets.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Disease-associated GWAS SNV enrichment.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“N = 2139 Class 2 genes”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
plainn = 2,139- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Cortical plate and germinal zone loops were then merged to create a master set of 24,544 loops spanning the two brain tissues.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Disease-associated GWAS SNV enrichment.
What the sources say
- Not checked yetcites [41] Won, H. et al. Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538, 523–527 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“5C maps from our mature primary cortical neurons were highly correlated with and exhibited similar loops as published Hi-C maps from ES cell-derived cortical neurons”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > 3D genome maps of dynamic loops during cortical neuron inhibition and activation.
What the sources say
- Not checked yetcites [33] Bonev, B. et al. Multiscale 3D genome rewiring during mouse neural development. Cell 171, 557–572 e524 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that, within our 5C regions, activity-induced loops are rare and connect to genes with large activity-dependent increases in expression, whereas pre-existing loops are more abundant but correlate with only minor gene expression changes.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Unique architectural motifs connect activity-dependent genes and enhancers.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“thus loop dysfunction could be possible owing to common SNVs in sporadic ASD and schizophrenia.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In the ABC model, the multiplication of enhancer activity and 3D interaction frequency was the best predictor of enhancer–target gene pairs37.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
What the sources say
- Not checked yetcites [37] Fulco, C. P. et al. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat. Genet. 51, 1664–1669 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Genome misfolding has been reported in fragile X syndrome48, the leading monogenic cause of ASD, as well as other human diseases49”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
What the sources say
- Not checked yetcites [48] Sun, J. H. et al. Disease-associated short tandem repeats co-localize with chromatin domain boundaries. Cell 175, 224–238.e15 (2018). source
- Not checked yetcites [49] Norton, H. K. & Phillips-Cremins, J. E. Crossed wires: 3D genome misfolding in human disease. J. Cell Biol. 216, 3441–3452 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“H3K27ac enrichment was confirmed before sequencing by querying the immunoprecipitation or input quantitative PCR (qPCR) enrichment of primer pairs designed to the Arc, synaptotagmin 1, and Tcf25 promoter regions.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > ChIP–seq library preparation.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We note that the Arc interaction falls below our 30-kb distance threshold and therefore is not formally added to the class 1 loop list”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“More than 90% of disease-associated SNVs (daSNVs) are localized in noncoding regions with unknown target genes40”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Neuropsychiatric-disease-associated genetic variants colocalize with distinct classes of activity-dependent, looped enhancers.
What the sources say
- Not checked yetcites [40] Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, our 5C results suggest that loops that are induced by neural stimulation are relatively rare but exhibit a markedly higher effect on activity-dependent upregulation of distal target genes.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data are consistent with our working model in which SRGs engage in a complex network of long-range loops, whereas IEGs form simple, short-range loops to activity-induced enhancers to facilitate rapid activation independent of new protein synthesis”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > IEGs form shorter and less complex loops than SRGs.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that rapid activity-induced enhancer switching via alternative looping might be a mechanistic aspect of IEG upregulation”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, Bdnf loop and enhancer dynamics are significantly delayed in comparison to those of Fos and Arc, corroborating our model that slower interaction kinetics may contribute to SRGs delayed expression.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Results > Differential IEG and SRG looping kinetics after an acute neural activation time course.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Consistent with our observations, another study reported—using H3K4me3 proximity ligation assisted ChIP–seq (PLAC-seq)—that the SRG Nr4a3 engages in multiple long-range contacts over several hundred kb after neuronal stimulation26.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Discussion
What the sources say
- Not checked yetcites [26] Yamada, T. et al. Sensory experience remodels genome architecture in neural circuit to drive motor learning. Nature 569, 708–713 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Results were consistent across 2 culture batches, 4 total 5C replicates, 3 RNA-seq replicates, and H3K27ac ChIP replicate analyzed.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment conditions were evenly distributed across culture batches and treatments were randomly assigned to culture dishes within each batch.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Statistics.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“No statistical methods were used to pre-determine sample sizes but our sample sizes are similar to those reported in previous publications17,27,28.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Statistics.
What the sources say
- Not checked yetcites [17] Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014). source
- Not checked yetcites [27] Beagan, J. A. et al. YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment. Genome Res 27, 1139–1152 (2017). source
- Not checked yetcites [28] Beagan, J. A. et al. Local genome topology can exhibit an incompletely rewired 3D-folding state during somatic cell reprogramming. Cell Stem. Cell 18, 611–624 (2016). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Resulting P values were corrected for multiple testing using the Benjamini–Hochberg procedure.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Hi-C loop calling.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data collection and analysis were not performed blind to the conditions of the experiments.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Statistics.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Residuals were plotted to confirm approximate normal distributions.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Linear regression modeling.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, genes were not considered if they fell within 200 kb of the edges of our 5C regions because we could not accurately capture their looping profiles.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Activity-dependent loop classification and gene expression analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No animals or data points were excluded from the analyses.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > Statistics.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To minimize and identify technical variation, three replicates spanning two culture batches were prepared, pooled, and sequenced to depths of greater than 60 million reads per library.”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > RNA-seq library preparation.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
H3K27ac signal correlates with enhancer and promoter activity.
“As the histone mark H3 lysine 27 acetylation (H3K27ac) correlates with enhancer and promoter activity”
The paper relies on this without support.
Activity-dependent enhancer classes identified in mouse cortical neurons correspond to functionally equivalent regulatory elements in human brain.
“We lifted-over our activity-dependent enhancer classes to the human genome and classified 4,098 class 2 and 3,822 class 3 loops from human brain tissue”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“There is now emerging evidence that the 3D genome is actively regulated during learning and memory formation”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [38]
Experimental — accuracy not yet measuredIn the citing paper
“The 3D genome plays an important role in neuronal gene expression and function”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [38]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Methods > IEG and SRG analysis.
“We analyzed rapid IEGs (defined as rIEGs in ref. 9), translation-independent SRGs (tiSRG, defined as dPRG in ref. 9) and translation-dependent SRGs (tdSRG, defined as SRG in ref. 9)”
§ Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression > Extended Data
“rapid immediate early genes (rIEGs, as defined as rPRGs in Tyssowski et al.9)”
Citations
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Fast gapped-read alignment with Bowtie 2
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STAR: ultrafast universal RNA-seq aligner
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Model-based Analysis of ChIP-Seq (MACS)
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Salmon provides fast and bias-aware quantification of transcript expression
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A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping
Rao, S. S. P., Huntley, M. H., Durand, N. C., Stamenova, E. K., Bochkov, I. D., Robinson, J. T., Sanborn, A. L., Machol, I., Omer, A. D., Lander, E. S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.021 · Cited by 9,212
Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome
Lieberman-Aiden, E., van Berkum, N. L., Williams, L., Imakaev, M., Ragoczy, T., Telling, A., Amit, I., Lajoie, B. R., Sabo, P. J., Dorschner, M. O., et al. (2009) · Science · doi:10.1126/science.1181369 · Cited by 8,898
deepTools2: a next generation web server for deep-sequencing data analysis
Ramírez, F., Ryan, D. P., Grüning, B., Bhardwaj, V., Kilpert, F., Richter, A. S., Heyne, S., Dündar, F., & Manke, T. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw257 · Cited by 8,096
An integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829
Cited by
Sorted by citations
Kundaković, M., & Rocks, D. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.101010 · Cited by 356
DNA G-quadruplex structures: more than simple roadblocks to transcription?
Robinson, J., Raguseo, F., Nuccio, S. P., Liano, D., & Antonio, M. D. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab609 · Cited by 321
Functional inference of gene regulation using single-cell multi-omics
Kartha, V. K., Duarte, F. M., Hu, Y., Ma, S., Chew, J. G., Lareau, C. A., Earl, A., Burkett, Z. D., Kohlway, A. S., Lebofsky, R., et al. (2022) · Cell Genomics · doi:10.1016/j.xgen.2022.100166 · Cited by 224
Cell-type specialization is encoded by specific chromatin topologies
Winick‐Ng, W., Kukalev, A., Harabula, I., Zea-Redondo, L., Szabó, D., Meijer, M., Serebreni, L., Zhang, Y., Bianco, S., Chiariello, A. M., et al. (2021) · Nature · doi:10.1038/s41586-021-04081-2 · Cited by 214
The spatial organization of transcriptional control
Hafner, A., & Boettiger, A. N. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00526-0 · Cited by 158
Metadata
- Authors
- Beagan, J. A., Pastuzyn, E. D., Fernandez, L. R., Guo, M. H., Feng, K., Titus, K. R., Chandrashekar, H., Shepherd, J. D., & Phillips-Cremins, J. E.
- Affiliations
- University of Pennsylvania (US)
- University of Utah (US)
- Hospital of the University of Pennsylvania (US)
- Corresponding author
- Shepherd, Jason D.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2020-05-25
- Volume
- 23
- Issue
- 6
- Pages
- 707-717
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC7558717
- OpenAlex
- W3027029189
- Cited by
- 143
- References
- 69
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 23 · 2023: 29 · 2022: 28 · 2021: 23 · 2020: 7
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-07-23)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U01HL129998)
- National Institute of Mental Health (DP2MH110247, R01MH112766)
- National Institute of Neurological Disorders and Stroke (R01NS114226)
- National Institute of Biomedical Imaging and Bioengineering (T32EB009384)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- 3D genome organization, activity-dependent gene expression, immediate early genes, FOS, Arc, brain-derived neurotrophic factor, chromatin remodeling, transcriptional kinetics, single nucleotide variants, autism spectrum disorder, schizophrenia, cortical neurons
- MeSH terms
- Animals, Bicuculline, Cytoskeletal Proteins, Humans, Nerve Tissue Proteins, Neurons, Tetrodotoxin, Time Factors, Gene Expression, Genome, Proto-Oncogene Proteins c-fos, Brain-Derived Neurotrophic Factor, Chromatin Assembly and Disassembly, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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