The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index; 3 of the 17 sources its claims cite were checked for support.
Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens
Open accessPublished version of a preprint
Abstract
CRISPR screens have been used to connect genetic perturbations with changes in gene expression and phenotypes. Here we describe a CRISPR-based, single-cell combinatorial indexing assay for transposase-accessible chromatin (CRISPR-sciATAC) to link genetic perturbations to genome-wide chromatin accessibility in a large number of cells. In human myelogenous leukemia cells, we apply CRISPR-sciATAC to target 105 chromatin-related genes, generating chromatin accessibility data for ~30,000 single cells. We correlate the loss of specific chromatin remodelers with changes in accessibility globally and at the binding sites of individual transcription factors (TFs). For example, we show that loss of the H3K27 methyltransferase EZH2 increases accessibility at heterochromatic regions involved in embryonic development and triggers expression of genes in the HOXA and HOXD clusters. At a subset of regulatory sites, we also analyze changes in nucleosome spacing following the loss of chromatin remodelers. CRISPR-sciATAC is a high-throughput, single-cell method for studying the effect of genetic perturbations on chromatin in normal and disease states.
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45 Own result · 9 Not checked yet · 6 Own interpretation · 4 Own method · 3 Supported · 3 No basis given
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In the paper
“However, methods to capture changes in the epigenome following CRISPR perturbations have limited throughput6.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
What the sources say
- Supportedcites [6] Rubin, A. J. et al. Coupled single-cell CRISPR screening and epigenomic profiling reveals causal gene regulatory networks. Cell 176, 361–376 (2019). source
The Introduction says epigenetic assays are difficult to couple with genetic perturbations at scale, leaving most studies to test single perturbations in bulk populations. The Discussion likewise says earlier approaches required perturbing candidate factors one by one. These passages support the claim about the limited throughput of prior methods; the paper presents Perturb-ATAC as a higher-throughput response. (LLM, conf=0.90)
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“The consortium performed association testing for 19,960 genes expressed in blood in 31,684 samples44.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > eQTL enrichment
What the sources say
- Supportedcites [44] Võsa, U. et al. Unraveling the polygenic architecture of complex traits using blood eQTL meta-analysis. Preprint at bioRxiv https://doi.org/10.1101/447367 (2018). source
The Empirical probe matching section states that 19,960 genes were tested in the combined meta-analyses. The Main text reports that the eQTLGen Consortium conducted those analyses in 31,684 blood samples from 37 cohorts. (LLM, conf=0.93)
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In the paper
“and triggers expression of genes in the HOXA and HOXD clusters.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
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“We correlate loss of specific chromatin remodelers with changes in accessibility globally and at the binding sites of individual transcription factors.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
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“In human myelogenous leukemia cells, we apply CRISPR-sciATAC to target 105 chromatin-related genes, generating chromatin accessibility data for ~30,000 single cells.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
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“we show that loss of the H3K27 methyltransferase EZH2 increases accessibility at heterochromatic regions involved in embryonic development”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
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“We found that 93% of cell barcodes had gRNA-containing reads that could uniquely be assigned to either human or mouse gRNAs”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
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“Here, we describe a CRISPR-based single-cell combinatorial indexing assay for transposase-accessible chromatin (CRISPR-sciATAC) to link genetic perturbations to genome-wide chromatin accessibility in a large number of cells.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
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“The majority of cell barcodes (83%) had one gRNA”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
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“A similar increase in accessibility was also seen at the HOXD gene cluster”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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In the paper
“Loss of SMARCA5, which helps load cohesin onto chromosomes20, triggered a reduction in accessibility in binding sites of cohesin subunits RAD21 and SMC3 along with cohesin cofactor ZNF14321.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > A loss-of-function screen of chromatin remodeling complexes using CRISPR-sciATAC
What the sources say
- Not checked yetcites [20] Hakimi, M. A. et al. A chromatin remodelling complex that loads cohesin onto human chromosomes. Nature 123, 3175–3184 (2002).
- Not checked yetcites [21] Wen, Z., Huang, Z. T., Zhang, R. & Peng, C. ZNF143 is a regulator of chromatin loop. Cell Biol. Toxicol. 34, 471–478 (2018). source
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“loss of EP400, which is part of the Sick With Rat8ts (SWR) complex, causes a large, 56 nt expansion of nucleosomes around AP-1 binding sites (p = 10−4)”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Quantifying nucleosome movement at transcription factor binding sites following chromatin remodeler loss
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In the paper
“across all CRISPR perturbations, the expansion of nucleosome spacing around AP-1 binding sites occurs mostly in sites that are located in promoters”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Quantifying nucleosome movement at transcription factor binding sites following chromatin remodeler loss
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“We also noticed that large changes in TF accessibility correlate with decreased cell proliferation”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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“found that increased accessibility in Polycomb repressive complex 1 (PRC1) components CBX2 and CBX8 binding sites has the highest predictive power in differentiating EZH2-targeted cells.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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In the paper
“we find that loss of ARID1A dramatically reduced accessibility at enhancers, but not at promoters”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > A loss-of-function screen of chromatin remodeling complexes using CRISPR-sciATAC
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In the paper
“We found similar changes in TFBS accessibility using either ENCODE ChIP-seq data from K562 or predicted TF binding sites (JASPAR TF motifs13 and chromVAR14)”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
What the sources say
- Not checked yetcites [13] Mathelier, A. et al. JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 44, D110–D115 (2016). source
- Not checked yetcites [14] Schep, A. N., Wu, B., Buenrostro, J. D. & Greenleaf, W. J. ChromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat. Methods 14, 975–978 (2017). source
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“we computed gene-level enrichment scores (Supplementary Fig. 4e, Supplementary Table 3), which were highly correlated with a previous genome-wide CRISPR screen in K562 cells10 (r = 0.85)”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
What the sources say
- Not checked yetcites [10] Wang, T. et al. Identification and characterization of essential genes in the human genome. Science 350, 1096–1101 (2015). source
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In the paper
“As expected, we find an increase in accessibility at EZH2 binding sites”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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In the paper
“In the HOXA gene cluster, we found that there was a nearly 3-fold increase in accessibility”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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“In line with a previous study36, we found that glyoxal fixation resulted in better preservation of intact nuclei than the more commonly used paraformaldehyde fixative.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > CRISPR-sciATAC species mixing experiment in HEK293 and NIH3T3 cells
What the sources say
- Not checked yetcites [36] Richter, K. N. et al. Glyoxal as an alternative fixative to formaldehyde in immunostaining and super‐resolution microscopy. EMBO J. 37, 139–159 (2017). source
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In the paper
“In contrast, expansion of nucleosome spacing around ZNF143 binding sites occurs mostly in sites that are located in enhancers.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Quantifying nucleosome movement at transcription factor binding sites following chromatin remodeler loss
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“A two-dimensional UMAP projection of the TFBS accessibility profiles reveals a cluster enriched in SWI/SNF components and, in particular, pBAF components (hypergeometric p = 4 × 10−4)”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > A loss-of-function screen of chromatin remodeling complexes using CRISPR-sciATAC
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“we captured paired CRISPR perturbation and single-cell ATAC-seq data from 16,676 cells.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > A loss-of-function screen of chromatin remodeling complexes using CRISPR-sciATAC
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“The chromatin accessibility profiles resulting from TnY and Tn5 are highly correlated”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Transposase identification and isolation
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“After EZH2 loss, we found that these previously-silenced genes become highly expressed.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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“Using Gene Ontology (GO) analysis of differentially accessible regions in EZH2-targeted cells, we found an enrichment in genes involved in embryonic development and cell differentiation”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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“In contrast, knock-out of BAF/pBAF subunit SMARCB1 tends to cause nucleosome expansion around TFBSs in enhancers but not in promoters (e.g. at RAD21 sites)”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Quantifying nucleosome movement at transcription factor binding sites following chromatin remodeler loss
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“96% of cell barcodes had ATAC-seq reads mapping to either the human or mouse genome”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
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“ARID1A loss results in a 20 nt nucleosome compaction at AP-1 binding sites (p = 0.03)”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Quantifying nucleosome movement at transcription factor binding sites following chromatin remodeler loss
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“The ViPar transposase with P50K and M53Q mutations, henceforth referred to as TnY, showed Tn5 ME loading and tagmentation activity”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Transposase identification and isolation
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“Combining data from both CRISPR-sciATAC experiments, we found that the chromatin modifiers targeted in our two screens resulted in a greater number of accessibility changes at enhancers than at promoters”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > A loss-of-function screen of chromatin remodeling complexes using CRISPR-sciATAC
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“In K562 cells, the HOXA and HOXD gene clusters contain the highest amount of H3K27me3 repressive heterochromatin.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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“Hierarchical clustering of single cells transduced with EZH2-targeting gRNAs or non-targeting gRNAs reveals a clear separation”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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“we observe an increase in accessibility at only PU.1 binding sites upon loss of RCOR1”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > A loss-of-function screen of chromatin remodeling complexes using CRISPR-sciATAC
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“KDM6A-targeted cells had the largest reduction of cis-eQTL accessibility with eQTL genes (eGenes) involved in DNA condensation and chemokine receptor activity”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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“with the exception of BAF/pBAF (SWI/SNF) subunits ARID1A and PBRM1 where knock-out leads to compaction of nucleosomes around the TFBSs studied”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Quantifying nucleosome movement at transcription factor binding sites following chromatin remodeler loss
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“Targeting the Polycomb repressive complex 2 (PRC2) subunit EZH2 resulted in an increase in chromatin accessibility at regions with H3K27me3”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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In the paper
“we found that loss of chromatin remodelers generally results in expansion of nucleosomes around TFBSs”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Quantifying nucleosome movement at transcription factor binding sites following chromatin remodeler loss
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“A downsampling analysis reveals that for some target genes, like EZH2 and ARID1A, a small number of cells correlates well (rp ≥ 0.75) to an aggregated (pseudo-bulk) cell population (5 single cells for EZH2, 25 single cells for ARID1A)”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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“Reassuringly, enrichment of individual gRNAs was positively correlated with cell numbers estimated from CRISPR-sciATAC cell barcodes (r = 0.73, Supplementary Fig. 4g).”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
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“we found that changes in accessibility in single cells at transcription factor binding site (TFBS) are consistent between gRNAs targeting the same gene”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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- 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 for 92% of the captured cell barcodes both ATAC-seq and gRNA reads aligned either to human or mouse reference genomic and gRNA sequences, respectively.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
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 focused on a small subset of 7 TFs with NFR score of more than zero, and indeed, for the binding sites of TFs, we observe strong bimodality.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Nucleosome dynamics at TFBS, promoters and enhancers
boosted- 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
“For two of our targets — KDM6A and ARID1A — we found a reduction in accessibility at tissue-matched (blood) cis-eQTLs in cells after perturbation of these genes”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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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
“CRISPR-sciATAC is a high-throughput single-cell method for studying the role of genetic perturbations on chromatin in normal and disease states.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
plain- 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
“supporting a gene regulatory model with more dynamic chromatin accessibility at distal regulatory elements compared to promoters18.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > A loss-of-function screen of chromatin remodeling complexes using CRISPR-sciATAC
What the sources say
- Not checked yetcites [18] Nord, A. S. et al. Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell 155, 1521–1531 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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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
“The low rates of these two failure modes suggest that CRISPR-sciATAC can simultaneously identify accessible chromatin and CRISPR gRNAs in single cells.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
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.
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
“Taken together, these results suggest that loss-of-function mutations in EZH2 lead to aberrant expression of genes from HOXA and HOXD clusters.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
hedgeddirect- 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: CRISPR nuclease-induced loss of a chromatin modifier in K562 cells models loss-of-function mutations in cancer.
In the paper
“EZH2 catalyzes nucleosome compaction via H3K27 trimethylation11”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
What the sources say
- Not checked yetcites [11] Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011). source
plaindirect- 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
“In this work, we develop CRISPR-sciATAC, a platform for pooled forward genetic screens that jointly captures CRISPR perturbations and ATAC profiles in single cells.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Discussion
plain- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 8
- The quote only partly states this claim. 1
- It may state two separate claims as one. 12
Every source the paper cites for this claim was checked and supports it.
In the paper
“Alterations in chromatin state have been associated with many diseases including several cancers1.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
What the sources say
- Supportedcites [1] Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380 (2017). source
The Introduction states that chromatin aberrations are associated with a wide range of common diseases, including cancer. It also describes chromatin alterations across human cancers, supporting the claim’s reference to several cancers. (LLM, conf=0.94)
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.
- Supported
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 a subset of regulatory sites, we also analyze changes in nucleosome spacing upon loss of chromatin remodelers.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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The quote only partly states this 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
“When compared with Perturb-ATAC, CRISPR-sciATAC can generate thousands of single cells at ~20x less reagent cost and requires ~14x less time (Supplementary Tables 8 and 9).”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Discussion
plaindirect- 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
“we found that TnY has insertion site preferences distinct from, but of a similar magnitude to those of Tn5”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Transposase identification and isolation
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
“Loss of SWI/SNF-ATPase subunit ARID1A or ISWI-ATPase subunit SMARCA5 results in many changes in TFBS accessibility”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > A loss-of-function screen of chromatin remodeling complexes using CRISPR-sciATAC
plaindirect- 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
“Knock-out of CoREST subunit SFMBT1 tends to cause nucleosome expansion around TFBSs in promoters but not in enhancers, for the 7 TFs analyzed: for example, an 85 nt expansion around AP-1 binding sites in promoters and no change in nucleosomal positions around AP-1 binding sites in enhancers”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Quantifying nucleosome movement at transcription factor binding sites following chromatin remodeler loss
hedgedconditional- 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
“In this work, we analyzed 28,510 cells, which is ~7-fold more cells than in the Perturb-ATAC dataset”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Discussion
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
“After filtering for cells with ≥500 unique ATAC-seq fragments and ≥100 gRNA reads (Supplementary Fig. 3c–h), we obtained 11,104 cells with a median of 1,977 unique ATAC-seq fragments mapping to the human genome.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
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
“Among the 3 gRNAs targeting EZH2, we noticed that the least effective gRNA resulted in less HOX gene expression, further reinforcing the role of EZH2 in maintaining HOX gene repression”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > Loss of chromatin modifiers alters chromatin accessibility at regulatory elements in single cells
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.
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 recovered all 66 gRNAs with a median of 148 single cells per gRNA and 468 single cells per gene.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Results > CRISPR-sciATAC captures both chromatin accessibility profiles and CRISPR perturbations in single cells
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In recent years, CRISPR screens have been combined with single-cell RNA-sequencing to measure the effects of genetic perturbations on gene expression across the transcriptome2–5.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Abstract
What the sources say
- Not checked yetcites [2] Datlinger, P. et al. Pooled CRISPR screening with single-cell transcriptome readout. Nat. Methods 14, 297–301 (2017). source
- Not checked yetcites [3] Adamson, B. et al. A multiplexed single-cell CRISPR screening platform enables systematic dissection of the unfolded protein response. Cell 167, 1867–1882 (2016). source
- Not checked yetcites [4] Dixit, A. et al. Perturb-seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens. Cell 167, 1853–1866 (2016). source
- Not checked yetcites [5] Jaitin, D. A. et al. Dissecting immune circuits by linking CRISPR-pooled screens with single-cell RNA-seq. Cell 167, 1883–1896 (2016). source
plaindirect- 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
“one important caveat of CRISPR nuclease-driven perturbation is that knock-out can be incomplete due to in-frame repair and efficiency can vary depending on the gRNA.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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
“Overall, CRISPR-sciATAC can be applied to study diverse phenotypes and diseases and to understand the interaction between genetic changes and genome-wide chromatin accessibility.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
In the paper
“The p-values were adjusted for multiple hypothesis testing using a Benjamini-Hochberg false-discovery rate correction (q ≤ 0.1).”
- Also stated in: § Statistical analysis · plain
“Corrections for multiple-hypothesis testing was performed using the Benjamini-Hochberg approach48.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Differential accessibility at genomic regions with specific chromatin and DNA modifications
What the sources say
- Not checked yetcites [48] Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B Stat. Methodol. 57, 289–300 (1995). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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Probably not a substantial claim.
- Also stated in: § Statistical analysis · plain
In the paper
“These TFs have also been previously shown to have a bimodal profile24.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Nucleosome dynamics at TFBS, promoters and enhancers
What the sources say
- Not checked yetcites [24] Kundaje, A. et al. Ubiquitous heterogeneity and asymmetry of the chromatin environment at regulatory elements. Genome Res. 22, 1735–1747 (2012). 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.
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
“However, CRISPR-sciATAC does not depend critically on any specific gRNA but rather looks for consistent effects between gRNAs.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Discussion
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.
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
“Empirical p-values for each score were generated using a label-permutation test, where non-targeting and knock-out labels were randomly shuffled while keeping group size constant to avoid biases that stem from different numbers of cells in the non-targeting and knock-out cell populations.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Nucleosome dynamics at TFBS, promoters and 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.
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
“The gRNA library coverage was 1,500x on average for the species-mixing experiment, the chromatin modifier screen and the chromatin remodeling complex subunit screen.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Lentiviral CRISPR libraries
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
“To avoid biases from recovery of different numbers of cells for each gRNA, we subsampled all gRNA cell populations to 12 cells (the lowest number of cells for a single gRNA in our K562 dataset), calculated the deviation Z-scores, and repeated this resampling process 1000 times to obtain deviation Z-scores for each gRNA.”
§ Profiling the genetic determinants of chromatin accessibility with scalable single-cell CRISPR screens > Methods > Differential accessibility in TF binding sites using JASPAR motifs
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.
The paper relies on this without support.
Chromatin accessibility controls gene expression and is dynamically regulated during differentiation and homeostasis.
“Chromatin accessibility orchestrates cis- and trans-regulatory interactions to control gene expression and is dynamically regulated in cell differentiation and homeostasis.”
The paper relies on this without support.
CRISPR nuclease-induced loss of a chromatin modifier in K562 cells models loss-of-function mutations in cancer.
“Taken together, these results suggest that loss-of-function mutations in EZH2 lead to aberrant expression of genes from HOXA and HOXD clusters.”
The paper relies on this without support.
The presence of a gRNA in a cell indicates functional perturbation of the targeted gene.
“CRISPR-sciATAC does not depend critically on any specific gRNA but rather looks for consistent effects between gRNAs.”
The paper relies on this without support.
ENCODE ChIP-seq data from K562 accurately represents the chromatin marks in the studied K562 cells.
“We examined how loss of these chromatin modifiers impacts accessibility within known chromatin marks (primarily histone post-translation modifications) using ENCODE ChIP-seq data from K562 cells”
The paper relies on this without support.
Non-targeting gRNAs have no effect on chromatin accessibility.
“For cells receiving a non-targeting gRNA, we find that 75 cells correlate well with the respective pseudo-bulk populations”
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
“identified five methods commonly in use: the default Seurat [19] FindMarkers() function based on the Wilcoxon test (Seurat-Wilcox), MIMOSCA [1], a t-test on the library-size-normalized expressions [10], MAST [20], and a Kolmogorov-Smirnov (KS) test on the library-size-normalized expressions [21]”
From Robust differential expression testing for single-cell CRISPR screens at low multiplicity of infection (2024) · cites this paper as [10]
Experimental — accuracy not yet measuredIn the citing paper
“We included scATAC-seq data from three different sources: Spear-ATAC42, CRISPR-sciATAC59 and ASAP-seq39.”
From scPerturb: harmonized single-cell perturbation data (2024) · cites this paper as [59]
In the citing paper
“A similar approach involves CRISPR screens with CRISPR–sciATAC [21], which enables the joint capture of chromatin accessibility profiles and CRISPR perturbations.”
From A mini-review on perturbation modelling across single-cell omic modalities (2024) · cites this paper as [21]
In the citing paper
“Compared to Perturb-ATAC, both Spear-ATAC and CRISPR–sciATAC offer higher throughput.”
From A mini-review on perturbation modelling across single-cell omic modalities (2024) · cites this paper as [21]
In the citing paper
“Furthermore, CRISPR–sciATAC can generate thousands of single cells at ∼20 × less reagent cost and requires ∼14 × less time than Perturb-ATAC.”
From A mini-review on perturbation modelling across single-cell omic modalities (2024) · cites this paper as [21]
Citations
Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
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Thompson, J. D., Higgins, D. G., & Gibson, T. J. (1994) · Nucleic Acids Research · doi:10.1093/nar/22.22.4673 · Cited by 64,617
Fast gapped-read alignment with Bowtie 2
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BEDTools: a flexible suite of utilities for comparing genomic features
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Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013) · Nature Methods · doi:10.1038/nmeth.2688 · Cited by 6,422
The GTEx Consortium atlas of genetic regulatory effects across human tissues
The GTEx Consortium, Aguet, F., Anand, S., Ardlie, K. G., Gabriel, S., Getz, G. A., Graubert, A., Hadley, K., Handsaker, R. E., Huang, K. H., et al. (2020) · Science · doi:10.1126/science.aaz1776 · Cited by 5,547
Genome-scale CRISPR-Cas9 knockout screening in human cells
Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., et al. (2014) · Science · doi:10.1126/science.1247005 · Cited by 5,234
Self-citationGOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists
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The Polycomb complex PRC2 and its mark in life
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Cited by
Sorted by citations
Methods and applications for single-cell and spatial multi-omics
Vandereyken, K., Sifrim, A., Thienpont, B., & Voet, T. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-023-00580-2 · Cited by 1,244
Bock, C., Datlinger, P., Chardon, F. M., Coelho, M. A., Dong, M. B., Lawson, K. A., Lu, T., Maroc, L., Norman, T. M., Song, B., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-021-00093-4 · Cited by 641
Bock, C., Datlinger, P., Chardon, F. M., Coelho, M. A., Dong, M. B., Lawson, K. A., Lu, T., Maroc, L., Norman, T. M., Song, B., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00098-7 · Cited by 264
Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens
Morris, J. A., Caragine, C., Daniloski, Z., Domingo, J., Barry, T., Lu, L., Davis, K., Ziosi, M., Glinos, D. A., Hao, S., et al. (2023) · Science · doi:10.1126/science.adh7699 · Cited by 208
Self-citationscPerturb: harmonized single-cell perturbation data
Peidli, S., Green, T. D., Shen, C., Gross, T., Min, J., Garda, S., Yuan, B., Schumacher, L. J., Taylor-King, J. P., Marks, D. S., et al. (2024) · Nature Methods · doi:10.1038/s41592-023-02144-y · Cited by 194
Metadata
- Authors
- Liscovitch-Brauer, N., Montalbano, A., Deng, J., Méndez-Mancilla, A., Wessels, H.-H., Moss, N. G., Kung, C.-Y., Sookdeo, A., Guo, X., Geller, E., Jaini, S., Smibert, P., & Sanjana, N. E.
- Affiliations
- New York Genome Center (US)
- Corresponding author
- Sanjana, Neville E.
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2021-04-29
- Volume
- 39
- Issue
- 10
- Pages
- 1270-1277
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC8516442
- OpenAlex
- W3158694246
- Cited by
- 107
- References
- 52
- Citations by year
- 2026: 10 · 2025: 31 · 2024: 30 · 2023: 14 · 2022: 17 · 2021: 5
- FWCI
- 5.49
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Biotechnology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Human Frontier Science Program (LT000672/2019-L)
- European Molecular Biology Organization (ALTF 826-2018)
- U.S. Department of Health & Human Services | National Institutes of Health (DP2HG010099, R01CA218668)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- chromatin accessibility, single-cell CRISPR screens, chromatin remodelers, EZH2, H3K27 methylation, heterochromatin, transcription factor binding sites, nucleosome spacing, myeloid leukemia
- MeSH terms
- RNA-Seq, Binding Sites, Chromatin, Humans, Leukemia, Myeloid, Nucleosomes, Transcription Factors, Transposases, Gene Expression Profiling, Chromatin Assembly and Disassembly, Regulatory Elements, Transcriptional, Epigenomics, Single-Cell Analysis, Clustered Regularly Interspaced Short Palindromic Repeats
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 2026-10-04, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-04 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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