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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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A Phase Separation Model for Transcriptional Control
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“Many demonstrations of the modular and additive behavior of enhancers exist, both for elements controlling the same locus across different tissues and for simultaneously active individual elements within a super-enhancer (for example, Hay et al., 2016; Maeda and Karch, 2011; Visel et al., 2009).”
BackgroundStructural variation in the 3D genome
Spielmann, M., Lupiáñez, D. G., & Mundlos, S. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0007-0 · Cited by 752
Enhancer redundancy provides phenotypic robustness in mammalian development
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“Founder (F0) mice were genotyped using PCR with High Fidelity Platinum Taq Polymerase (Thermo Fisher Scientific) to identify those with the desired non-homologous end joining (NHEJ)-generated deletion breakpoints (see Extended Data Figs 1a–j, 5a–c, 7a, d and Supplementary Table 3 for genotyping strategy, primer sequen…”
MethodInfluentialSelf-citationMultiplexed Engineering and Analysis of Combinatorial Enhancer Activity in Single Cells
Xie, S., Duan, J., Li, B., Zhou, P., & Hon, G. C. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.03.007 · Cited by 334
“These results are consistent with recent reports (Hay et al., 2016; Hnisz mbination with sgRNAs targeting PIM1 SE2 (right).”
ResultThe AP-1 transcriptional complex: Local switch or remote command?
Bejjani, F., Evanno, E., Zibara, K., Piechaczyk, M., & Jariel‐Encontre, I. (2019) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2019.04.003 · Cited by 370
Super-Enhancer-Driven Transcriptional Dependencies in Cancer
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Regulation of disease-associated gene expression in the 3D genome
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“Examples of genes that depend on multiple enhancers for expression in a single tissue include the α and βglobin genes 31,33 , Wap (encoding whey acidic protein) 30 and Aicda (encod ing activationinduced cytidine deaminase) 34 .”
The relationship between genome structure and function
Oudelaar, A. M., & Higgs, D. R. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00303-x · Cited by 304
Self-citationDeciphering the multi-scale, quantitative cis-regulatory code
Kim, S., & Wysocka, J. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.032 · Cited by 302
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“OCT4 peaks were annotated as putative promoters or putative distal regulatory elements in a manner similar to that described previously (Hay et al., 2016), using the relative and absolute coverage of H3K4me3 (a promoter-associated modification; Yue et al.”
MethodSuper-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis
Suzuki, H. I., Young, R. A., & Sharp, P. A. (2017) · Cell · doi:10.1016/j.cell.2017.02.015 · Cited by 284
“…recent reports have explored the contribution of the constituent enhancers of SEs to expression of mRNA transcripts, with varying results (Hay et al., 2016; Hnisz et al., 2015; Shin et al., 2016); it remains unclear whether multiple SE constituents have redundant or non-redundant…”
Dissecting super-enhancer hierarchy based on chromatin interactions
Huang, J., Li, K., Cai, W., Liu, X., Zhang, Y., Orkin, S. H., Xu, J., & Yuan, G.-C. (2018) · Nature Communications · doi:10.1038/s41467-018-03279-9 · Cited by 241
“In some studies, the results are consistent with a model whereby SEs are composed of a hierarchy of both essential and dispensable constituent enhancers to coordinate gene transcription (Hay et al., 2016; Hnisz et al., 2015; Huang et al., 2016; H. Y. Shin et al., 2016).”
BackgroundResultEnhancer redundancy in development and disease
Kvon, E. Z., Waymack, R., Gad, M., & Wunderlich, Z. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00311-x · Cited by 247
Transposable elements as a potent source of diverse cis -regulatory sequences in mammalian genomes
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Evaluating Enhancer Function and Transcription
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“Four of these enhancers (R1, R2, R3 and Rm) lie within the introns of an adjacent widely expressed gene (Nprl3)15.”
Self-citationCatarino, R. R., & Stark, A. (2018) · Genes & Development · doi:10.1101/gad.310367.117 · Cited by 215
“…deletion of individual constituent enhancers within SEs revealed that enhancer activity is mostly dependent on a few constituents that activate transcription predominately additively (Hnisz et al. 2015; Hay et al. 2016; Moorthy et al. 2017; Xie et al. 2017; for discussion, see Dukler et al. 2016).”
BackgroundSuper-enhancers include classical enhancers and facilitators to fully activate gene expression
Blayney, J. W., Francis, H., Rampasekova, A., Camellato, B., Mitchell, L., Stolper, R., Cornell, L., Babbs, C., Boeke, J. D., Higgs, D. R., et al. (2023) · Cell · doi:10.1016/j.cell.2023.11.030 · Cited by 196
“16,17 As we have shown here, this level of dissection is insufficient to unequivocally conclude whether a cluster combines additively or non-additively.”
BackgroundInfluentialSelf-citationSingle-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains
Oudelaar, A. M., Davies, J. O. J., Hanssen, L. L. P., Telenius, J. M., Schwessinger, R., Liu, Y., Brown, J. M., Downes, D. J., Chiariello, A. M., Bianco, S., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0253-2 · Cited by 196
Epigenetics of Atherosclerosis: Emerging Mechanisms and Methods
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“Furthermore, Hay et al. (2016) showed by deletions within the Hba super-enhancer that each constituent enhancer acts independently in an additive manner to regulate expression of Hba genes in vivo.”
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Kron, K. J., Murison, A. J., Zhou, S., Huang, V., Yamaguchi, T. N., Shiah, Y.-J., Fraser, M. E., van der Kwast, T., Boutros, P. C., Bristow, R. G., et al. (2017) · Nature Genetics · doi:10.1038/ng.3930 · Cited by 189
Polymer Simulations of Heteromorphic Chromatin Predict the 3D Folding of Complex Genomic Loci
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Defining genome architecture at base-pair resolution
Peng, H., Badat, M., Hanssen, L. L. P., Hentges, L. D., Crump, N. T., Downes, D. J., Jeziorska, D. M., Oudelaar, A. M., Schweßinger, R., Taylor, S., et al. (2021) · Nature · doi:10.1038/s41586-021-03639-4 · Cited by 189
Self-citationLoss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder
Long, H. K., Osterwalder, M., Welsh, I. C., Hansen, K. L., Davies, J. O. J., Liu, Y. E., Koska, M., Adams, A. T., Aho, R., Arora, N., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.09.001 · Cited by 166
Self-citationEnhancer Logic and Mechanics in Development and Disease
Rickels, R. A., & Shilatifard, A. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.04.003 · Cited by 171
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Unraveling Hematopoiesis through the Lens of Genomics
Liggett, L. A., & Sankaran, V. G. (2020) · Cell · doi:10.1016/j.cell.2020.08.030 · Cited by 163
“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).”
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Generating specificity in genome regulation through transcription factor sensitivity to chromatin
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Enhancer grammar in development, evolution, and disease: dependencies and interplay
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“Other aspects of transcriptional regulation that may affect enhancer grammar include enhancer-enhancer interactions, additive or synergistic activity of enhancers, and transvection (Fukaya and Levine, 2017; Hay et al., 2016; Maekawa et al., 1989).”
BackgroundSuper-enhancers in transcriptional regulation and genome organization
Wang, X., Cairns, M. J., & Yan, J. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1038 · Cited by 154
Reconstruction of the Global Neural Crest Gene Regulatory Network In Vivo
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Self-citationPeng, L., Jiang, B., Yuan, X., Qiu, Y., Peng, J., Huang, Y., Zhang, C., Zhang, Y., Lin, Z., Li, J., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0367 · Cited by 140
Genome-wide mapping of autonomous promoter activity in human cells
van Arensbergen, J., FitzPatrick, V. D., de Haas, M., Pagie, L., Sluimer, J., Bussemaker, H. J., & van Steensel, B. (2017) · Nature Biotechnology · doi:10.1038/nbt.3754 · Cited by 140
An encyclopedia of enhancer-gene regulatory interactions in the human genome
Gschwind, A. R., Mualim, K. S., Karbalayghareh, A., Sheth, M. U., Dey, K. K., Jagoda, E., Nurtdinov, R. N., Xi, W., Tan, A. S., Jones, H., et al. (2023) · doi:10.1101/2023.11.09.563812 · Cited by 119
The three-dimensional genome: regulating gene expression during pluripotency and development
Andrey, G., & Mundlos, S. (2017) · Development · doi:10.1242/dev.148304 · Cited by 134
“…vivo studies of the α-globin gene locus, which is controlled by a cluster of enhancer elements, also referred to as a super enhancer, have shown that each enhancer seems to act independently and in an additive fashion without clear evidence of synergistic or higher-order effects (Hay et al., 2016).”
BackgroundWill, A. J., Cova, G., Osterwalder, M., Chan, W.-L., Wittler, L., Brieske, N., Heinrich, V., de Villartay, J., Vingron, M., Klopocki, E., et al. (2017) · Nature Genetics · doi:10.1038/ng.3939 · Cited by 126
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Novo, C. L., Javierre, B.-M., Cairns, J., Segonds-Pichon, A., Wingett, S. W., Freire-Pritchett, P., Furlan-Magaril, M., Schoenfelder, S., Fraser, P., & Rugg-Gunn, P. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.040 · Cited by 119
“Equally, questions have been raised as to whether SEs should be considered as separate entities from clusters of canonical enhancers or locus control regions (Moorthy et al., 2017; Bojcsuk et al., 2017; Hay et al., 2016; Pott and Lieb, 2015), and thus, it is fundamental to investigate the properties of SEs.”
BackgroundDynamics of the 4D Genome during in Vivo Lineage Specification and Differentiation
Oudelaar, A. M., Beagrie, R. A., Gosden, M., de Ornellas, S., Georgiades, E., Kerry, J., Hidalgo, D., Carrelha, J., Shivalingam, A., El-Sagheer, A. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16598-7 · Cited by 119
Self-citationNested epistasis enhancer networks for robust genome regulation
Lin, X., Liu, Y., Liu, S., Zhu, X., Wu, L., Zhu, Y., Zhao, D., Xu, X., Chemparathy, A., Wang, H., et al. (2022) · Science · doi:10.1126/science.abk3512 · Cited by 112
Evidence for additive and synergistic action of mammalian enhancers during cell fate determination
Choi, J., Lysakovskaia, K., Stik, G., Demel, C., Söding, J., Tian, T. V., Graf, T., & Cramer, P. (2021) · eLife · doi:10.7554/elife.65381 · Cited by 117
“In contrast to our time-resolved study, previous studies investigated enhancer cooperation in steady state or at an end point, and at selected genes, rather than genome-wide (Hay et al., 2016; Osterwalder et al., 2018; Stine et al., 2011).”
BackgroundResultTranscriptional Regulation by (Super)Enhancers: From Discovery to Mechanisms
Grosveld, F., van Staalduinen, J., & Stadhouders, R. (2021) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-122220-093818 · Cited by 115
Carleton, J. B., Berrett, K. C., & Gertz, J. (2017) · Cell Systems · doi:10.1016/j.cels.2017.08.011 · Cited by 113
“In dissection of the murine alpha globin enhancer (Hay et al., 2016), as well as enhancers near the c-fos gene (Joo et al., 2016), similar seemingly non-functional regulatory elements were identified, suggesting that these sites may be a pervasive feature of mammalian genomes.”
BackgroundGillespie, M. A., Palii, C. G., Sanchez-Taltavull, D., Shannon, P., Longabaugh, W. J. R., Downes, D. J., Sivaraman, K., Espinoza, H. M., Hughes, J. R., Price, N. D., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.03.031 · Cited by 110
Self-citationThomas, H. F., Kotova, E., Jayaram, S., Pilz, A., Romeike, M., Lackner, A., Penz, T., Bock, C., Leeb, M., Halbritter, F., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2020.12.047 · Cited by 98
Transcription imparts architecture, function and logic to enhancer units
Tippens, N. D., Liang, J. H., Leung, A. K.-Y., Wierbowski, S. D., Ozer, A., Booth, J. G., Lis, J. T., & Yu, H. (2020) · Nature Genetics · doi:10.1038/s41588-020-0686-2 · Cited by 104
Targeting Super-Enhancers for Disease Treatment and Diagnosis.
Shin, H. Y. (2018) · Europe PMC (PubMed Central) · doi:10.14348/molcells.2018.2297 · Cited by 101
“However, individual constituent super-enhancers in erythroid cells showed independent functions without any hierarchy, indicating that the constituent enhancers function differently in different cell types or under different environments (Hay et al., 2016).”
BackgroundTesting the super-enhancer concept
Blobel, G. A., Higgs, D. R., Mitchell, J. A., Notani, D., & Young, R. A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00398-w · Cited by 98
Self-citationKLF1 drives the expression of fetal hemoglobin in British HPFH
Wienert, B., Martyn, G. E., Kurita, R., Nakamura, Y., Quinlan, K. G. R., & Crossley, M. (2017) · Blood · doi:10.1182/blood-2017-02-767400 · Cited by 94
Li, P., Mitra, S., Spolski, R. J., Oh, J., Liao, W., Tang, Z., Mo, F., Li, X., West, E. E., Gromer, D. J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1714019114 · Cited by 94
Self-citationOudelaar, A. M., Harrold, C. L., Hanssen, L. L. P., Telenius, J. M., Higgs, D. R., & Hughes, J. R. (2019) · Nature Communications · doi:10.1038/s41467-019-13404-x · Cited by 80
“The α-globin genes and their five enhancer elements, which fulfil the criteria for a super-enhancer (Hay et al., 2016), are located in a small TAD which is activated during erythroid differentiation (Brown et al., 2018).”
BackgroundSelf-citationOncogenic super-enhancer formation in tumorigenesis and its molecular mechanisms
Jia, Q., Chen, S., Tan, Y., Li, Y., & Tang, F. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0428-7 · Cited by 92
Transcription factor competition at the γ-globin promoters controls hemoglobin switching
Liu, N., Xu, S., Yao, Q., Zhu, Q., Yan, K., Hsu, J. Y., Sakon, P., Pinello, L., Yuan, G., Bauer, D. E., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00798-y · Cited by 86
Ober-Reynolds, B., Wang, C., Ko, J. M., Rios, E. J., Aasi, S. Z., Davis, M. M., Oro, A. E., & Greenleaf, W. J. (2023) · Nature Genetics · doi:10.1038/s41588-023-01445-4 · Cited by 83
“These findings support an additive, modular model of enhancer activity—a model substantiated by genetic perturbation studies of individual enhancers for alpha-globin 37 and Myc 38 , studies of enhancers involved in limb development 39 and genomic-scale measures of enhancer activity 40,41 .”
Current challenges in understanding the role of enhancers in disease
Zaugg, J. B., Sahlén, P., Andersson, R., Alberich-Jordà, M., de Laat, W. L., Deplancke, B., Ferrer, J. P., Mandrup, S., Natoli, G., Plewczyński, D., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00896-3 · Cited by 86
“As a consequence of such regulatory complexity, many enhancers might not, individually, reveal a strong phenotype when disrupted in their endogenous context 23,56 , while still possessing endogenous enhancer activity.”
BackgroundA suite of enhancer AAVs and transgenic mouse lines for genetic access to cortical cell types
Ben‐Simon, Y., Hooper, M. J., Narayan, S., Daigle, T. L., Dwivedi, D., Way, S. W., Oster, A., Stafford, D. A., Mich, J. K., Taormina, M. J., et al. (2025) · Cell · doi:10.1016/j.cell.2025.05.002 · Cited by 85
“61,62 To diversify the use of our enhancer-based genetic toolkit, we replaced SYFP2 with a Cre recombinase, which would enable expression of a variety of tools from existing or newly generated Cre-dependent AAVs or mouse transgenes.”
Transcriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81
“Likewise, the transcriptional effects of enhancer deletions within extended super-enhancer loci are also consistent with the generally additive effects of individual enhancers [517, 518].”
BackgroundKrüppel-like factors compete for promoters and enhancers to fine-tune transcription
Ilsley, M. D., Gillinder, K. R., Magor, G. W., Huang, S., Bailey, T. L., Crossley, M., & Perkins, A. C. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx441 · Cited by 81
Mammalian Transcription Factor Networks: Recent Advances in Interrogating Biological Complexity
Wilkinson, A. C., Nakauchi, H., & Göttgens, B. (2017) · Cell Systems · doi:10.1016/j.cels.2017.07.004 · Cited by 76
“However, the functional relevance of this 9 classification is still unclear (Hay et al., 2016).”
BackgroundIs a super-enhancer greater than the sum of its parts?
Dukler, N., Gulko, B., Huang, Y.-F., & Siepel, A. (2017) · Nature Genetics · doi:10.1038/ng.3759 · Cited by 79
Enhancer and super‐enhancer: Positive regulators in gene transcription
Peng, Y., & Zhang, Y. (2018) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12032 · Cited by 78
Anania, C., Acemel, R. D., Jedamzick, J., Bolondi, A., Cova, G., Brieske, N., Kühn, R., Wittler, L., Real, F. M., & Lupiáñez, D. G. (2022) · Nature Genetics · doi:10.1038/s41588-022-01117-9 · Cited by 79
Enhancers and chromatin structures: regulatory hubs in gene expression and diseases
Hu, Z., & Tee, W. (2017) · Bioscience Reports · doi:10.1042/bsr20160183 · Cited by 80
Pijuan-Sala, B., Wilson, N. K., Xia, J., Hou, X., Hannah, R., Kinston, S., Calero‐Nieto, F. J., Poirion, O., Preißl, S., Liu, F., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0489-9 · Cited by 73
LDB1-mediated enhancer looping can be established independent of mediator and cohesin
Krivega, I. V., & Dean, A. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx433 · Cited by 75
Sancisi, V., Manzotti, G., Gugnoni, M., Rossi, T., Gandolfi, G., Gobbi, G., Torricelli, F., Catellani, F., do Valle, Í. F., Remondini, D., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx802 · Cited by 75
Perenthaler, E., Yousefi, S., Niggl, E., & Barakat, T. S. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00352 · Cited by 75
“On the other hand, an increasing number of studies have challenged this view and consider super enhancers as a collection of normal enhancers that together do not have a larger activity than the sum of the individual parts (Hay et al., 2016; Shin et al., 2016).”
BackgroundBrown, J. M., Roberts, N. A., Graham, B., Waithe, D., Lagerholm, C., Telenius, J. M., De Ornellas, S., Oudelaar, A. M., Scott, C., Szczerbal, I., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06248-4 · Cited by 72
Benton, M. L., Talipineni, S. C., Kostka, D., & Capra, J. A. (2019) · BMC Genomics · doi:10.1186/s12864-019-5779-x · Cited by 70
“We also consider a method that incorporates DNase I hypersensitive sites (DHSs) with histone modifications to generate the “ DNasePlusHistone ” enhancer set, which is composed of DHSs where the ratio of H3K4me1 to H3K4me3 is less than one [36].”
MethodVisualizing transcription: key to understanding gene expression dynamics
Brouwer, I., & Lenstra, T. L. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.05.031 · Cited by 73
Santos, M. D., Backer, S., Aurade, F., Wong, M. M.-K., Wurmser, M., Pierre, R., Vives, F. L., Cruzeiro, M. D., Schmitt, A., Concordet, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28666-1 · Cited by 75
Synthetic regulatory genomics uncovers enhancer context dependence at the Sox2 locus
Brosh, R., Coelho, C., Ribeiro-dos-Santos, A. M., Ellis, G., Hogan, M. S., Ashe, H. J., Somogyi, N., Ordóñez, R., Luther, R. D., Huang, E., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.02.027 · Cited by 75
Enhancers: bridging the gap between gene control and human disease
Karnuta, J. M., & Scacheri, P. C. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy167 · Cited by 77
“There appears to be no common regulatory modality; some act additively like those at the a-globin locus (28), and others work synergistically, like those at the mammary Wap locus (29).”
BackgroundStudying Transcriptional Enhancers: The Founder Fallacy, Validation Creep, and Other Biases
Halfon, M. S. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.11.004 · Cited by 66
Matthews, B. J., & Waxman, D. J. (2018) · eLife · doi:10.7554/elife.34077 · Cited by 66
Mechanisms of Enhancer-Promoter Interactions in Higher Eukaryotes
Georgiev, P. G., & Kyrchanova, O. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020671 · Cited by 72
Transcription factors: building hubs in the 3D space
Giammartino, D. C. D., Polyzos, A., & Apostolou, E. (2020) · Cell Cycle · doi:10.1080/15384101.2020.1805238 · Cited by 67
Genetic Dissection of a Super Enhancer Controlling the Nppa-Nppb Cluster in the Heart
Man, J. C. K., van Duijvenboden, K., Krijger, P. H. L., Hooijkaas, I. B., van der Made, I., Vries, C. D. G.-D., Wakker, V., Creemers, E. E., de Laat, W. L., Boukens, B. J., et al. (2020) · Circulation Research · doi:10.1161/circresaha.120.317045 · Cited by 65
Vos, E. S. M., Valdes‐Quezada, C., Huang, Y., Allahyar, A., Verstegen, M. J. A. M., Felder, A.-K., van der Vegt, F., Uijttewaal, E. C. H., Krijger, P. H. L., & de Laat, W. L. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.06.008 · Cited by 61
Chromatin priming of genes in development: Concepts, mechanisms and consequences
Bonifer, C., & Cockerill, P. N. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.01.003 · Cited by 63
Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture
Downes, D. J., Smith, A., Karpińska, M. A., Velychko, T., Rue-Albrecht, K., Sims, D., Milne, T. A., Davies, J. O. J., Oudelaar, A. M., & Hughes, J. R. (2022) · Nature Protocols · doi:10.1038/s41596-021-00651-w · Cited by 62
Self-citationPeng, X. L., So, K. K. H., He, L., Zhao, Y. F., Zhou, J., Li, Y., Yao, M., Xu, B., Zhang, S., Yao, H., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx488 · Cited by 64
Raffield, L. M., Ulirsch, J. C., Naik, R. P. P., Lessard, S., Handsaker, R. E., Jain, D., Kang, H. M., Pankratz, N., Auer, P. L., Bao, E. L., et al. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007293 · Cited by 65
Spatial Organization of Chromatin: Emergence of Chromatin Structure During Development
Ghosh, R. P., & Meyer, B. J. (2021) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-032321-035734 · Cited by 60
“Finally, emergent properties of liquid condensates formed at SE clusters are difficult to reconcile with the additive rather than collective impact of enhancers in SE clusters, as seen in case of globin genes (Hay et al. 2016).”
BackgroundDecreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice
Carrat, G., Hu, M., Nguyen‐Tu, M., CHABOSSEAU, P. L., Gaulton, K. J., van de Bunt, M., Siddiq, A., Falchi, M., Thurner, M., Canouil, M., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.01.011 · Cited by 62
“Raw FASTQ reads were processed with a departmental/in-house pipeline 42 and on the DNase and ChIP pipeline website (Web Resources).”
MethodSET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expressionPreprint
Cao, K., Collings, C. K., Marshall, S. A., Morgan, M. A., Rendleman, E. J., Wang, L., Sze, C. C., Sun, T., Bartom, E. T., & Shilatifard, A. (2017) · Genes & Development · doi:10.1101/gad.294744.116 · Cited by 61
“The redundancy observed for E1 and E2 is different from α-globin enhancers, which act in an additivemanner (Hay et al. 2016), suggesting the locus specificity of enhancer commissioning (Smith and Shilatifard 2014).”
BackgroundA model of active transcription hubs that unifies the roles of active promoters and enhancers
Zhu, I., Song, W., Ovcharenko, I., & Landsman, D. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab235 · Cited by 55
Influences of rare copy-number variation on human complex traits
Hujoel, M. L. A., Sherman, M. A., Barton, A. R., Mukamel, R. E., Sankaran, V. G., Terao, C., & Loh, P. (2022) · Cell · doi:10.1016/j.cell.2022.09.028 · Cited by 59
Regulating specificity in enhancer–promoter communication
Galouzis, C. C., & Furlong, E. E. M. (2022) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2022.01.010 · Cited by 61
Taylor, T., Sikorska, N., Shchuka, V. M., Chahar, S., Ji, C., Macpherson, N. N., Moorthy, S. D., de Kort, M. A. C., Mullany, S., Khader, N., et al. (2022) · Genes & Development · doi:10.1101/gad.349489.122 · Cited by 45
“…enhancers is markedly de-bated, 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; for discussion, see Blobel et al. 2021).”
Reactivation of a developmentally silenced embryonic globin gene
King, A. J., Songdej, D., Downes, D. J., Beagrie, R. A., Liu, S., Buckley, M., Peng, H., Suciu, M., Oudelaar, A. M., Hanssen, L. L. P., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24402-3 · Cited by 57
Self-citationEnhancer cooperativity can compensate for loss of activity over large genomic distances
Thomas, H., Feng, S., Haslhofer, F., Huber, M., Gallardo, M. G., Loubière, V., Vanina, D., Pitasi, M., Stark, A., & Buecker, C. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.11.008 · Cited by 59
Super-enhancers are transcriptionally more active and cell type-specific than stretch enhancers
Khan, A., Mathelier, A., & Zhang, X. (2018) · Epigenetics · doi:10.1080/15592294.2018.1514231 · Cited by 58
“Some studies have showed synergy and hierarchy between the individual enhancers within the clusters [23,43,44], but this synergy is less obvious for some developmentally regulated super-enhancers [45].”
Background
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
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