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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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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.
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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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“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.
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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
“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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- Rests on an assumption: H3K27ac signal correlates with enhancer and promoter activity.
- 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.
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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.
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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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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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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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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.
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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.
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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 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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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.
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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
“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.
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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.
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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.
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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
“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.
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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.
- 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.
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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.
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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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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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- 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.
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- 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.
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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.
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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.
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- 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)”
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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
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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.
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