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Genetic dissection of the α-globin super-enhancer in vivo
Open accessAbstract
Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. These super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. Our study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.
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Written from the paper’s full text.
TL;DR
A functional dissection of the mouse α-globin super-enhancer shows that its five constituent elements act independently and additively, with no evidence of synergistic or higher-order super-enhancer properties. Only R1 and R2 behave as strong enhancers in vivo, while R3, R4 and Rm contribute little or nothing to α-globin expression.
Key findings
- In primary mouse erythroid cells, 15,849 DNase I hypersensitive sites were identified; after filtering, 1,963 putative enhancers were defined, and 95 regions (<7%) were classified as super-enhancers by Med1 occupancy. The α- and β-globin regulatory regions were the two highest-scoring erythroid super-enhancers.
- The mouse α-globin super-enhancer spans 24 kb and contains five enhancer-like elements. R1 and R2 were strong enhancers in vivo; R3, R4 and Rm had little or no discernible impact on α-globin RNA synthesis, despite chromatin signatures and positive transient enhancer assays.
- Deletion of R1 or R2 individually caused significant, reproducible reductions in α-globin RNA synthesis and increased reticulocyte counts, while R1/R2 double homozygotes died in utero at ~E14.5 and produced very little α-globin RNA, with remaining <10% of normal α-globin RNA levels likely transcribed under intact cis-elements.
- Chromatin structure and chromosome conformation were largely independent of the intact super-enhancer: no individual hypersensitive site depended on any other, and even in R1/R2−/− cells, hypersensitive sites at R3, R4 and Rm still formed; Capture-C showed little change in the tissue-specific chromatin compartment.
Methods
- Mouse models: seven homologous-recombination models were generated, deleting each of the five α-globin super-enhancer elements singly (R1, R2, R3, Rm, R4) plus two informative double knockouts (R2/R3 and R1/R2).
- Data types: primary mouse erythroid cells were profiled by DNase I hypersensitivity, ChIP-seq for chromatin marks and transcription factors, ATAC-seq, and Next Generation Capture-C; enhancer activity was tested in transient chick reporter assays and stably integrated mouse LacZ transgenic assays.
- Expression and phenotype: hematologic parameters, reticulocyte counts, total and nascent RNA (4-thiouridine labeling followed by NanoString) were measured in fetal liver erythroid cultures and adult mice; statistical analysis used Levene’s test followed by one-way ANOVA with Dunnett’s correction.
Limitations
- Stated: the authors did not assess possible changes in Med1 binding, activating chromatin marks, or eRNA production in the context of each enhancer knockout; they also state that findings cannot be extrapolated to all super-enhancers.
- Stated: it remains possible that the apparently functionless elements have weak enhancer function not revealed by current physiological assays, or roles at different developmental stages or in defining enhancer polarity, which were not tested.
- Evident: the study is restricted to the mouse α-globin locus in erythroid cells, and conclusions about super-enhancer generality rely on this single locus plus prior β-globin LCR work; the authors call for genetic dissection of other super-enhancers in other cell types.
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Claims the paper makes
7 of 11 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“From the data presented here and from others29, 30, it seems likely that multiple enhancers may provide robustness in gene expression.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
What the sources say
- Supportedcites [29] Frankel, N. et al. Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466, 490–493 (2010). source
The paper’s Abstract reports that overlapping secondary enhancers support robust svb-dependent development under environmental and genetic perturbations. It also suggests that selection may maintain these enhancers for robustness against expression noise, supporting the citing sentence’s hedged claim about gene expression. (LLM, conf=0.88)
- Supportedcites [30] Perry, M.W., Boettiger, A.N., Bothma, J.P. & Levine, M. Shadow enhancers foster robustness of Drosophila gastrulation. Curr. Biol. 20, 1562–1567 (2010). source
The passage labeled Abstract states that BAC transgenes lacking either the primary or shadow enhancer show erratic transcription at elevated temperatures, and proposes that an additional enhancer suppresses expression noise. This supports the citing sentence’s hedged claim that multiple enhancers may provide robustness in gene expression. (LLM, conf=0.94)
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In the paper
“We would suggest, however, that these elements reflect evolutionary turnover in cis-acting elements as seen in other studies32.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
What the sources say
- Supportedcites [32] Villar, D. et al. Enhancer evolution across 20 mammalian species. Cell 160, 554–566 (2015). source
The Results section, “Recently Evolved Regulatory Activity Is Pervasive in Mammals” (page unavailable), reports abundant recently evolved enhancers. The Discussion section, “A Global Overview of Enhancer and Promoter Evolution in Mammals” (page unavailable), describes rapid enhancer evolution and short enhancer lifetimes. This supports the cited analogy of evolutionary turnover; the suggestion about the citing study’s own elements is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.88)
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: It is unlikely that cis-acting elements emerge fully formed during evolution or that they disappear entirely when they lose function.
- Supported
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
“Knockouts of R3, R4 and Rm appear to have little, if any, effect on α-globin expression or erythropoiesis.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > No single element is critical for globin gene expression
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In the paper
“Deletion of R4 has a minor impact.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > No single element is critical for globin gene expression
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In the paper
“Deletions of R3 and Rm, however, have no discernible impact on α-globin RNA synthesis (Fig. 5b).”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > No single element is critical for globin gene expression
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In the paper
“The previously reported α- and β-globin gene regulatory regions were the two highest scoring super-enhancers in erythroid cells using Mediator-binding as the defining parameter (Fig. 1c and Supplementary Table 1).”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > Five α-globin regulatory elements form an erythroid super-enhancer
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“Deletions of R1 and R2 have a significant and reproducible impact on the synthesis of α-globin RNA.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > No single element is critical for globin gene expression
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“These mice die in utero at ~E14.5”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > The enhancer elements act in an additive manner
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In the paper
“Analysis of α:β globin RNA ratios showed that R1/R2-/- fetal liver cells produced very little α-globin RNA (Fig. 5).”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > The enhancer elements act in an additive manner
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In the paper
“We find that no single element is critical for globin gene expression and, although each element scores as an erythroid enhancer based on conventional chromatin signatures and enhancer assays, only two of the five elements behave as strong enhancers in vivo during embryonic, fetal, and adult erythropoiesis.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Abstract
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- Probably not a substantial claim. 15
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Previous less extensive studies have also shown that the individual regulatory elements of the β-globin LCR, which we show here also corresponds to an erythroid super-enhancer, behave in a similar independent and additive manner28.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
What the sources say
- Supportedcites [28] Bender, M.A. et al. The hypersensitive sites of the murine β-globin locus control region act independently to affect nuclear localization and transcriptional elongation. Blood 119, 3820–3827 (2012). source
The Introduction says earlier single-site deletion studies suggested that each β-globin LCR hypersensitive site contributes additively to gene activation. The “HS contributions to LCR function” section reports that double-deletion results support independently acting modules with additive, rather than synergistic, effects. The super-enhancer description is the citing authors’ own framing, not a finding attributed to this source. (LLM, conf=0.93)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Sample sized were chosen with a view to detecting a 25% reduction in haemoglobin; smaller confirmatory datasets were obtained where the analysis of phenotype had already been reported (as for R2 and R3 deletions14, 19.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Hematologic analysis of mouse models
What the sources say
- Not checked — no full text of the sourcecites [14] Kowalczyk, M.S. et al. Intragenic enhancers act as alternative promoters. Mol. Cell 45, 447–458 (2012). source
- Could not verifycites [19] Anguita, E. et al. Deletion of the mouse α-globin regulatory element (HS −26) has an unexpectedly mild phenotype. Blood 100, 3450–3456 (2002). sourceExperimental — accuracy not yet measured
The Cytologic and hematologic analysis section describes how haemoglobin was measured, and the Results report haemoglobin findings, but neither states how sample sizes were chosen. Searches for a 25% reduction, sample-size planning, and a power calculation found no passage addressing the claimed detection target. The paper’s finding of essentially normal haemoglobin in untreated knockout mice does not establish what reduction the citing authors planned to detect. (LLM, conf=0.76)
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In the paper
“Indeed, it has been proposed that transcription factor hotspots, such as R1 and R2, create a permissive chromatin environment for the emergence of new transcription factor binding regions6.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
What the sources say
- Partly supportedcites [6] Siersbæk, R. et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 7, 1443–1455 (2014). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says transcription factors at hotspots cooperate in chromatin remodeling and establish an active epigenomic signature, supporting the idea of a permissive chromatin environment. Our copy does not identify hotspots R1 and R2 or say that hotspots enable new transcription factor binding regions to emerge. (LLM, conf=0.82)
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✗ Asserted: fails✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Hematologic phenotypes of a balanced mix of male and female mice for all models were examined at more than 7 weeks of age to avoid inter-individual variation42.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Hematologic analysis of mouse models
What the sources say
- Could not verifycites [42] Kent, W.J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002). sourceExperimental — accuracy not yet measured
The 'Tracks Based on Homology with Other Species' section discusses mouse genome sequence alignments, not hematologic testing in mice. Searches for hematologic phenotypes, the seven-week age threshold, and inter-individual variation found no passage addressing the claim in our copy. (LLM, conf=0.76)
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- Could not verify
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 the interactions between the α-globin promoters and the regions around the R1 and R2 enhancers are markedly reduced in R1/R2-/- cells, they remain above the baseline levels found in ES cells (Supplementary Fig. 6.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > The chromatin environment does not depend on the intact super-enhancer
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In the paper
“The mouse α-globin super-enhancer identified using these methods spans 24 kb and contains five enhancer-like elements, four of which lie in the introns of an adjacent, widely-expressed gene (Nprl3) (Fig. 1f).”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > Five α-globin regulatory elements form an erythroid super-enhancer
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In the paper
“We show that the presence of no individual hypersensitive site critically depends on any other: they appear to form independently.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > The chromatin environment does not depend on the intact super-enhancer
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In the paper
“In R2/R3-/-,cells, the promoters’ interactions with R1 are diminished but those with Rm and R4 are virtually unchanged compared to wild type.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > The chromatin environment does not depend on the intact super-enhancer
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“Further sub-classification of all erythroid enhancers shows that R1 and R2 are distinguished by binding the greatest number of cell-specific transcription factors and the greatest amount of Mediator, and they are also associated with the most extensively modified chromatin.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Analysis of the composition of regular enhancers and super-enhancers showed that, as expected, super-enhancers are enriched for composite enhancers (Fig. 1d); the greater the number of constituent elements, the more likely the region will be classified as a super-enhancer (Supplementary Fig. 1g).”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > Transcription factor binding varies between super-enhancer components
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None of the sources cited for this claim have been checked yet.
In the paper
“Previous less extensive studies have also shown that the individual regulatory elements of the β-globin LCR, which we show here also corresponds to an erythroid super-enhancer, behave in a similar independent and additive manner28.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Using the same methodology as described above to determine a cut-off, the four evolutionarily conserved α-globin regulatory elements (R1-4)16 still fell into the class of highly Med1 bound regions when analysed as single elements, whereas Rm (a species-specific cis-element) fell below the proposed criterion (Fig. 2b).”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > Transcription factor binding varies between super-enhancer components
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In the paper
“One puzzle emerging from this study is why enhancer-like elements which clearly score positively on indirect assays have no discernible function in their natural chromosomal environment.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
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In the paper
“Thus, despite their chromatin signatures, these three elements would not be classified as enhancers by this standard assay; only those two elements with the most extensive transcription factor binding profile as determined by PAM analysis scored positively in the assay.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > Enhancer assays do not reliably describe super-enhancer elements
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In the paper
“Similarly, removal of two elements does not appear to abrogate the formation of other enhancer elements showing that the cluster does not act as an interdependent holo-complex.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
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In the paper
“we have found that each element within the cluster appears to act independently rather than co-operatively, with removal of any one element having little or no effect on the function of the others.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
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In the paper
“Whereas R1 and R2 are strong enhancers in their natural chromosomal environment, R3, Rm and R4 are either very weak enhancers or are not enhancers at all, despite their chromatin marks.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
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In the paper
“Importantly we have shown that although all components of the cluster would be classified as enhancers they are not functionally equivalent.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Discussion
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In the paper
“Importantly, it can be seen that the super-enhancer does not act as a multi-component structure; removal of any single element cannot abolish its function.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Results > No single element is critical for globin gene expression
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In the paper
“Southern blotting was used to identify clones in which the second enhancer had been targeted in cis, and deleted in isolation, maintaining the coding sequence of Nprl3.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Generation of knockout mouse models
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In the paper
“The results were inspected, and used to validate the PAM clustering analysis.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Motif Analysis and Heatmaps
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In the paper
“All mouse work was performed in accordance with UK Home Office regulations under approved project licences.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Generation of knockout mouse models
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In the paper
“Southern blotting and sequencing were used to confirm the correct deletion.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Generation of knockout mouse models
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In the paper
“All mice were generated on the same complex background.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Hematologic analysis of mouse models
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In the paper
“Correctly targeted clones were identified by Southern blotting, and were karyotyped prior to blastocyst injection and chimera generation.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Generation of knockout mouse models
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In the paper
“The study of mammalian enhancers is hampered by the observation that these elements are defined by criteria only partially or indirectly related to their role in vivo9,10.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Abstract
What the sources say
- Not checked — no full text of the sourcecites [9] Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007). source
- Not checked — no full text of the sourcecites [10] Kvon, E.Z. Using transgenic reporter assays to functionally characterize enhancers in animals. Genomics 106, 185–192 (2015). source
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In the paper
“Reticulocyte preparations were made using Brilliant Cresyl Blue staining, and counts were made by two independent assessors blinded to genotype.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > Hematologic analysis of mouse models
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In the paper
“The clustering results were visually inspected, and validated in silhouette plots, and the best clustering (fewest outliers, high average silhouette value for all clusters) was seen when our annotated enhancers were divided to 16 clusters.”
§ Genetic dissection of the α-globin super-enhancer in vivo > Online Methods > PAM-clustering
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The paper relies on this without support.
It is unlikely that cis-acting elements emerge fully formed during evolution or that they disappear entirely when they lose function.
“It is unlikely that cis-acting elements emerge fully formed during evolution or that they disappear entirely when they lose function”
The paper relies on this without support.
The residual loxP site and multiple cloning site footprint left by the recombination do not affect local gene expression.
“This recombination leaves only a single residual loxP site and multiple cloning site footprint from the targeting vector.”
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In the citing paper
“Previous dissection of the endogenous α-SE, removing each of its constituents individually or in selective pairs, suggested that it is a cluster of five independent elements: two classical enhancers (R1 and R2) capable of significantly upregulating gene expression, and three inactive elements (R3, Rm, and R4)”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The α-SE is an ideal model for detailed genetic analysis, as its perturbation has no effect on cell identity or differentiation.17”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Review of diverse, albeit incomplete, previous analyses of SEs16,17,19,20,22 suggest that facilitators, as described here, may be relatively common elements in multipartite enhancers.”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The β-globin LCR includes six regulatory elements (HS1–6) and has been classified as a super-enhancer.17”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [17]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The mouse α-globin SE (α-SE) is made up of five constituent elements (R1, R2, R3, Rm, and R4)”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“Previous dissection of the α-SE suggested that its five constituents combine additively as independent elements,17”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“the transcriptional effects of enhancer deletions within extended super-enhancer loci are also consistent with the generally additive effects of individual enhancers [517, 518].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [517]
In the citing paper
“Furthermore, targeting disruption of specific enhancer elements has demonstrated that many of these long range regulatory elements additively enhance transcription (Hay et al., 2016) (Figure 4A).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Hay et al., 2016
In the citing paper
“We have shown that the α-globin genes are regulated by four conserved erythroid-specific enhancers (R1-R4) and a mouse specific element (Rm) located 14-38 kb upstream of the promoters15–17.”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [15]
In the citing paper
“Four of these enhancers (R1, R2, R3 and Rm) lie within the introns of an adjacent widely expressed gene (Nprl3)15.”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [15]
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Items 301–393 of 393
Aberrant Super-Enhancer Landscape in Enzalutamide-Resistant Prostate Cancer Cells
Cai, C., Liu, Q., Shan, H., Zheng, Y., Chen, G., Cai, Z., Zheng, Y., Lü, J., Tang, J., & Lin, Z. (2024) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2023.0280 · Cited by 2
“Interactions between TFs and the transcriptional machinery that are extremely well organized, especially master TFs, are required for SE-driven transcription regulation (Hay et al., 2016; Huang et al., 2018).”
Gunamalai, L., Singh, P., Berg, B., Shi, L., Sanchez, E., Smith, A., Breton, G., Bedford, M. T., Balciunas, D., & Kapoor, A. (2024) · Human Genetics and Genomics Advances · doi:10.1016/j.xhgg.2024.100358 · Cited by 2
“10 Although enhancer cooperation has been studied to some extent at the level of individual genes, 11,12 the nature of these combined effects from multiple enhancers and their variants remains functionally unexplored for most genes, especially for genes implicated for common diseases and traits by…”
Self-citationEnhancer‐dependent gene regulation in space, time, and malignancies
Blum, B., Dachtler, V., & Feldmann, A. (2025) · International Journal of Cancer · doi:10.1002/ijc.35350 · Cited by 2
Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis
Preston, A. E., Frost, J. N., Teh, M. R., Badat, M., Armitage, A. E., Norfo, R., Wideman, S. K., Hanifi, M., White, N., Roy, N. B. A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57683-z · Cited by 4
Self-citationMehra, P., & Kalani, A. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.09.021 · Cited by 2
Zeng, X., Lee, H., Wang, C., Achikeh, P., Liu, C., & Hennighausen, L. G. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0425-x · Cited by 2
‘Enhancing’ red cell fate through epigenetic mechanisms
Rossmann, M. P., & Zon, L. I. (2021) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000654 · Cited by 2
“Mouse in-vivo studies of the a-globin regulatory region that deleted single enhancer elements or combinations thereof and assayed globin expression and hemoglobin levels showed that individual enhancer elements functioned additively, with some of them (R1 and R2) having more pronounced effects on the a:b-globin ratio…”
BackgroundSegregation of α- and β-Globin Gene Cluster in Vertebrate Evolution: Chance or Necessity?
Iarovaia, O. V., Ulianov, S. V., Ioudinkova, E. S., & Razin, S. V. (2022) · Biochemistry (Moscow) · doi:10.1134/s0006297922090140 · Cited by 2
Enhancers predominantly regulate gene expression in vivo via transcription initiationPreprint
Larke, M., Nojima, T., Telenius, J. M., Sharpe, J. A., Sloane-Stanley, J. A., Butler, S., Beagrie, R. A., Downes, D. J., Schweßinger, R., Oudelaar, A. M., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/844191 · Cited by 2
Self-citationA mathematical model clarifies the ABC Score formula used in enhancer-gene predictionPreprint
Nasser, J., Nam, K.-M., & Gunawardena, J. (2025) · eLife · doi:10.7554/elife.105740.1 · Cited by 3
A body map of super-enhancers and their function in pig
Yang, Y., Li, X., Zhu, M., Liu, Y., Qian, K., Chu, M., & Pan, Z. (2023) · Frontiers in Veterinary Science · doi:10.3389/fvets.2023.1239965 · Cited by 2
Zebrafish for the Study of Enhancer Activity in Human Traits and Disease
Morice, E., Calhoun, C. C., Lalonde, R. L., & Leask, M. (2023) · IntechOpen eBooks · doi:10.5772/intechopen.1003949 · Cited by 1
Latt, K. Z., Yoshida, T., Shrivastav, S., Abedini, A., Reece, J. M., Sun, Z., Lee, H., Okamoto, K., Dagur, P. K., Ishimoto, Y., et al. (2024) · American Journal Of Pathology · doi:10.1016/j.ajpath.2024.06.006 · Cited by 1
Deleuze, V., Stephen, T., Salma, M., Orfeo, C., Jorna, R., Maas, A., Barroca, V., Arcangeli, M.-L., Lecellier, C., Andrieu‐Soler, C., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-94222-8 · Cited by 2
“…weak enhancer potential (such as the R4 α-globin enhancer) may actually play key roles as ‘facilitators’ by potentiating the activity of the strong typical enhancers (i.e. R2 enhancer) within the locus, although deletion of the R4 enhancer leads to very little impact on α-globin expression 11,12 .”
Molecular Characterization of Three Novel Large Deletions Causing α0-Thalassemia
Ferrer, S., Andrés, M. P. R., Murúzabal, M. J., Nieto, J. M., González, F. A., Montero, B. O., Villegas, A., Benavente, C., & Ropero, P. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26188783 · Cited by 1
“Functional studies have shown that deletion of this region has an impact comparable to that of complete structural deletions, both in cellular models and gene expression analyses in bone marrow [38,40].”
Himanen, S. V., Rabenius, A., Aktay, S., Tekoniemi, J., & Vihervaara, A. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116698 · Cited by 3
How to build the regulatory genome: a constructionist guide to the cis-regulatory code
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A functional overlap between actively transcribed genes and chromatin insulator elements
Cornell, L., Harrold, C. L., Holliman, S., Tsang, F. H., Gosden, M. E., Hanssen, L. E., Stolper, R. J., Downes, D. J., Biggs, D., Preece, C., et al. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00730-2 · Cited by 3
“Our previous studies of the mouse α - globin sub-TAD using chromosome conformation capture (Brown et al, 2018; Davies et al, 2016; Hanssen et al, 2017; Hay et al, 2016; Oudelaar et al, 2020; Oudelaar et al, 2018; Oudelaar et al, 2019) and super-resolution imaging (Brown et al, 2018) are entirely…”
InfluentialSelf-citationRobert, S. M., & Rada-Iglesias, Á. (2023) · BioEssays · doi:10.1002/bies.202300038 · Cited by 1
“However, neither gene reporter assays nor physical proximity can demonstrate whether an enhancer is necessary for the expression of a given gene, which requires the genetic or epigenetic disruption of the candidate enhancers.[14,15] Importantly, recent advances in CRISPR-based technologies and single-cell genomics ena…”
BackgroundEnhancer Activation by Transcription Factors and Underlying Mechanisms
Kondoh, H. (2024) · Results and problems in cell differentiation · doi:10.1007/978-3-031-39027-2_10 · Cited by 1
Liquid–liquid phase separation in normal hematopoiesis and hematological diseases
Lin, L., He, F., Xu, J., Zhang, X., Li, Y., Wang, D., Wang, J., Zheng, L., Song, H., Zhu, X. H., et al. (2025) · Cell and Tissue Research · doi:10.1007/s00441-025-03974-2 · Cited by 1
“Super-enhancers are defined as clusters of enhancer-like elements within a specific distance (5–12.5 kb) that bind primary regulators, such as Mediators or transcription factors (TFs), and are often flanked by CTCF-binding sites (Hay et al. 2016).”
InfluentialStart from Scratch: Precisely Identify Massive Active Enhancers by SequencingPreprint
Zhu, X., Huang, L., Li, Q., & Zhang, Y. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/604686 · Cited by 1
Nascent RNA 4sU labelling and enrichmentPreprint
Beagrie, R. A., & Downes, D. J. (2021) · doi:10.21203/rs.3.pex-1245/v1 · Cited by 1
chromMAGMA: regulatory element-centric interrogation of risk variantsPreprint
Nameki, R. A., Shetty, A. H., Dareng, E., Tyrer, J. P., Lin, X., Pharoah, P. D. P., Corona, R. I., Kar, S., & Lawrenson, K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.21.477270 · Cited by 1
Taylor, T., Sikorska, N., Shchuka, V. M., Chahar, S., Ji, C., Macpherson, N. N., Moorthy, S. D., Mitchell, J. A., & Sexton, T. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.02.09.479674 · Cited by 1
“…non-clustered enhancers is markedly debated, with previous genetic dissections uncovering context-dependent transcriptional effects that may be functionally redundant or additive, but not synergistic (Hay et al., 2016; Moorthy et al., 2017; Saravanan et al., 2020; discussed in Blobel et al., 2021).”
BackgroundSpolski, R. J., Li, P., Chandra, V., Shin, B., Liu, C., Oh, J., Ren, M., Enomoto, Y., West, E. E., Christensen, S. M., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.18.516445 · Cited by 1
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Large-scale analysis of the integration of enhancer-enhancer signals by promotersPreprint
Martinez-Ara, M., Comoglio, F., & van Steensel, B. (2024) · eLife · doi:10.7554/elife.91994.2 · Cited by 1
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CRISPRing the Human Genome for Functional Regulatory Elements
Lopes, R. (2018) · RePub (Erasmus University Rotterdam)
The Epigenetics of Autoimmunity and Epigenetic Drug Discovery
Tough, D. F., Rioja, I., Tak, P. P., & Prinjha, R. K. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809912-4.00015-5
Proofs of life: molecular-biology reasoning simulates cell behaviors from first principlesPreprint
Vestergaard, R., & Pietriga, E. (2018) · arXiv (Cornell University) · doi:10.48550/arxiv.1811.02478
“The requisite notion of compound contravariance is a combinatorial problem for MIG/RI specifications, cf. Ptashne [29], see Hay et al. [15].”
BackgroundIntegrative Modeling and Novel Technologies in Human Genomics
Carmona-Mora, P., & Young, J. I. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816573-7.00008-0
Regulatory plasticity within a complex cytokine-sensing mammary enhancer during lactationPreprint
Lee, H., Liu, C., & Hennighausen, L. G. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.04.134429
Li, H., Zeng, J., Zhao, Y., & Xu, X. (2020) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2020.102533
RetractedSkok, J. A. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.732585246.793545860
Kenter, A. L. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727835410.793558056
Are super-enhancers really super?
(2016) · Nature Methods · doi:10.1038/nmeth.3973
Mefford, H. C. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736437709.793571951
Blelloch, R. H. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727397521.793549797
Jiwu, L., Manna, S., Ying, Z., Fu, Y., Haiyang, C., Wanfang, X., & Yanhui, L. (2022) · Gene · doi:10.1016/j.gene.2022.146767
Ober-Reynolds, B., Wang, C., Ko, J., Rios, E. J., Aasi, S., Davis, M. M., Oro, A., & Greenleaf, W. (2022) · bioRxiv · doi:10.1101/2022.09.28.509620
HIV viral protein R induces loss of DCT1-type renal tubulesPreprint
Latt, K. Z., Yoshida, T., Shrivastav, S., Abedini, A., Reece, J. M., Sun, Z., Lee, H., Okamoto, K., Dagur, P. K., Heymann, J. A. W., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.02.526686
Non-coding variants impact cis -regulatory coordination in a cell type-specific mannerPreprint
Pushkarev, O., van Mierlo, G., Kribelbauer-Swietek, J. F., Saelens, W., Gardeux, V., & Deplancke, B. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.11.561870
Ancient Synteny Links Metabolism with Erythroid DevelopmentPreprint
Preston, A. E., Frost, J. N., Badat, M., Teh, M. R., Armitage, A. E., Norfo, R., Wideman, S. K., Hanifi, M., White, N., Roy, N. B. A., et al. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4615452
Self-citationXu, S., Ren, R., Peng, C., Lu, H., Ly, L. C., Crossley, M., Xu, B., Cheng, X., Blobel, G. A., & Lan, X. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.24.581901
Kim, S. K., Liu, T., Ou, F., Murphy, T. L., & MURPHY, K. M. M. (2024) · Advances in immunology · doi:10.1016/bs.ai.2024.08.001 · Cited by 1
A mathematical model clarifies the ABC Score formula used in enhancer-gene predictionPreprint
Nasser, J., Nam, K.-M., & Gunawardena, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.29.626072
“However, experimentally, a range of total fractional changes has been observed from 0 to greater than 3 [10, 11, 14, 21–23].”
Scarafia, M. A., Halek, J., Smucler, J., Waisman, A., Moro, L., Sevlever, G. E., Miriuka, S., & Greca, A. L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.24.630259
Zhao, S., Yang, Q., & Gao, C. (2025) · Revista de investigaci�n Cl�nica · doi:10.24875/ric.24000246
A mathematical model clarifies the ABC Score formula used in enhancer-gene predictionPreprint
Nasser, J., Nam, K.-M., & Gunawardena, J. (2025) · eLife · doi:10.7554/elife.105740 · Cited by 1
Snrnp25 is a candidate for the peri-implantation lethal phenotype of the Hba deletions
Velásquez-Escobar, A. M., Hillhouse, A., Magnuson, T., et al. (2025) · Mammalian Genome · doi:10.1007/s00335-025-10133-z
“Furthermore, the expression of alpha globin genes is highly regulated by a super-enhancer region within an intron of Nprl3 (Hay et al. 2016), which lies within the deletion boundaries.”
Leveraging chicken embryos for studying human enhancers
Williams, R. M. (2025) · Developmental Biology · doi:10.1016/j.ydbio.2025.05.009 · Cited by 1
Self-citationFunctional enhancers: concept, screening, and validation
Lin, H., Chen, F., & Huang, J. (2025) · Scientia Sinica Vitae · doi:10.1360/ssv-2025-0113
Molecular co-accessibility identifies coordinated regulation between distant cis-regulatory elementsPreprint
Boulanger, M., Chatsirisupachai, K., Badayeva, Y., Snajder, R., Bonder, M., Lapouge, K., Remans, K., & Krebs, A. R. (2025) · bioRxiv · doi:10.1101/2025.08.05.668660 · Cited by 2
“For instance, enhancer deletion studies have supported the additive model where multiple enhancers are required to reach sufficient levels of expression of the target gene, or to precisely modulate its expression at different times of development (5, 6, 8, 9).”
Specialised super-enhancer networks in stem cells and neuronsPreprint
Harabula, I., Speakman, L., Musella, F., Fiorillo, L., Zea-Redondo, L., Kukalev, A., Beagrie, R. A., Morris, K. J., Fernandes, L., Irastorza-Azcárate, I., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.13.670083
Matsuoka, K., Inoue, H., Hyejin, J., Okamoto, C., Hasuike, H., Fu, H. Y., Kioka, H., Kuramoto, Y., Segawa, T., Nishimura, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.13.682224
Characterization of a cis-regulatory element upstream of matrix metalloproteinase-9
Rangaraj, A., Kaur, H., Mejia, L., Hansen, J., Biswas, A., & Tuteja, G. (2025) · Scientific Reports · doi:10.1038/s41598-025-31297-3
Pushkarev, O., van Mierlo, G., Kribelbauer, J. F., Saelens, W., Gardeux, V., & Deplancke, B. (2024) · Figshare · doi:10.6084/m9.figshare.26333222
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Pushkarev, O., van Mierlo, G., Kribelbauer, J. F., Saelens, W., Gardeux, V., & Deplancke, B. (2024) · Figshare · doi:10.6084/m9.figshare.26750702
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Pushkarev, O., van Mierlo, G., Kribelbauer, J. F., Saelens, W., Gardeux, V., & Deplancke, B. (2024) · Figshare · doi:10.6084/m9.figshare.26750696
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Pushkarev, O., van Mierlo, G., Kribelbauer, J. F., Saelens, W., Gardeux, V., & Deplancke, B. (2024) · Figshare · doi:10.6084/m9.figshare.26750711
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Chick gonad explant electroporation reveals enhancers for testes determining factor, DMRT1
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Targeting enhancer RNAs to silence transcription
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Metadata
- Authors
- Hay, D., Hughes, J. R., Babbs, C., Davies, J. O. J., Graham, B. J., Hanssen, L. L. P., Kassouf, M. T., Oudelaar, A. M., Sharpe, J. A., Suciu, M. C., Telenius, J., Williams, R., Rode, C., Li, P.-S., Pennacchio, L. A., Sloane-Stanley, J. A., Ayyub, H., Butler, S., Sauka-Spengler, T., Gibbons, R. J., Smith, A. J. H., Wood, W. G., & Higgs, D. R.
- Venue
- Nature Genetics
- Published
- 2016-07-04
- Volume
- 48
- Issue
- 8
- Pages
- 895-903
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5058437
- OpenAlex
- W2464000940
- Cited by
- 385
- References
- 42
- Citations by year
- 2026: 20 · 2025: 37 · 2024: 36 · 2023: 36 · 2022: 44 · 2021: 46 · 2020: 40 · 2019: 28 · 2018: 41 · 2017: 41 · 2016: 16
- FWCI
- 18.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.osti.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- PubMed Central (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, DE-AC02-)
- Wellcome Trust (106130/Z/14/Z)
- National Institute for Health and Care Research
- National Institutes of Health (DE-AC02–05CH11231, R01-HG003988, U54 HG006997)
- Medical Research Council (MC_PC_15069, MR/N00969X/1, DE-AC02-05CH11231)
- Biomedical Research Council
- National Human Genome Research Institute (DE-AC02-05CH11231, U54HG006997, R01-HG003988)
- National Institute of Dental and Craniofacial Research (U01 DE020060, DE-AC02-05CH11231)
- Lawrence Berkeley National Laboratory (AC02‐05CH11231, DE-AC02-05CH11231, U54HG006997, R01HG003988, 05CH11231)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- super-enhancers, enhancer deletion, erythroid cells, hematological phenotype, chromatin structure, chromosome conformation, Mediator complex, transcriptional regulation, gene expression
- MeSH terms
- Animals, Chromatin, Embryo, Mammalian, Enhancer Elements, Genetic, Gene Expression Regulation, Transcription Factors, Transcription, Genetic, Mice, Knockout, Erythroid Cells, Mice, alpha-Globins
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 2026-10-27, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-27 (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.
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