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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 201–300 of 393
Ruffo, P., Traynor, B. J., & Conforti, F. L. (2025) · Genes & Diseases · doi:10.1016/j.gendis.2025.101652 · Cited by 15
“71,72 Therefore, the debate on whether SEs are a new class of non-coding regulatory elements or whether they reflect a clustering of normal non-coding regulatory elements within proximity remains to be resolved.”
Jeziorska, D. M., Tunnacliffe, E., Brown, J. M., Ayyub, H., Sloane-Stanley, J. A., Sharpe, J. A., Lagerholm, B. C., Babbs, C., Smith, A. J. H., Buckle, V. J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33977-4 · Cited by 18
“Early in erythroid differentiation (hereafter referred to as erythropoiesis) a ∼65 kb topologically associating sub-domain (sub-TAD) containing the entire mouse α-globin locus forms (Brown et al., 2018; Hay et al., 2016).”
BackgroundSelf-citationRecent Approaches for Manipulating Globin Gene Expression in Treating Hemoglobinopathies
Mussolino, C., & Strouboulis, J. (2021) · Frontiers in Genome Editing · doi:10.3389/fgeed.2021.618111 · Cited by 14
“Of these elements, only two, typically referred to as Multispecies Conserved Sequence R1 and R2 (MCS-R1 and MCS-R2), are able to drive α-globin expression at high levels and behave as strong enhancers (Hay et al., 2016).”
BackgroundCisinteractions in theIrf8locus regulate stage-dependent enhancer activationPreprint
Liu, T., Ou, F., Belk, J. A., Bagadia, P., Anderson, D. A., Durai, V., Yao, W., Satpathy, A. T., Murphy, T. L., & MURPHY, K. M. M. (2023) · Genes & Development · doi:10.1101/gad.350339.122 · Cited by 13
“In the Myc and α-globin superenhancers, individual constituents cooperated in an additive manner (Hay et al. 2016; Bahr et al. 2018).”
BackgroundMultiomics and deep learning dissect regulatory syntax in human development
Liu, B. B., Jessa, S., Kim, S. H., Ng, Y. T., Higashino, S. I., Marinov, G. K., Chen, D. C., Parks, B. E., Li, L., Nguyen, T. C., et al. (2026) · Nature · doi:10.1038/s41586-026-10326-9 · Cited by 36
“5l), consistent with the essential role of GATA1 in erythropoiesis and supporting its contribution to α-globin gene activation in this context 33 .”
Self-citationPolymer models are a versatile tool to study chromatin 3D organization
Esposito, A., Bianco, S., Fiorillo, L., Conte, M., Abraham, A., Musella, F., Nicodemi, M., Prisco, A., & Chiariello, A. M. (2021) · Biochemical Society Transactions · doi:10.1042/bst20201004 · Cited by 14
Understanding fundamental principles of enhancer biology at a model locus
Kassouf, M. T., Ford, S., Blayney, J., & Higgs, D. R. (2023) · BioEssays · doi:10.1002/bies.202300047 · Cited by 13
Self-citationThe α-globin super-enhancer acts in an orientation-dependent manner
Kassouf, M. T., Francis, H. S., Gosden, M. E., Suciu, M., Downes, D. J., Harrold, C. L., Larke, M., Oudelaar, A. M., Cornell, L., Blayney, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56380-1 · Cited by 16
Self-citationMaking connections: enhancers in cellular differentiation
Herrmann, J. C., Beagrie, R. A., & Hughes, J. R. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.10.008 · Cited by 14
Self-citationHuang, Y. L., Koues, O. I., Zhao, J., Liu, R., Pyfrom, S., Payton, J. E., & Oltz, E. M. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.067 · Cited by 13
“Furthermore, it remains controversial whether SEs represent a new paradigm in transcriptional regulation or merely clusters of CEs that additively promote transcription (Dukler et al., 2016; Hay et al., 2016).”
Chong-Morrison, V., Simões, F. C., Senanayake, U., Carroll, D. S., Riley, P. R., & Sauka‐Spengler, T. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/450684 · Cited by 13
“…the functional relationship between sox10 E2, E5 and E7 enhancers, characterised by our Ac/Ds enhancer assay, and endogenous sox10 expression using our optimised CRISPRi approach (Fig.4A), as enhancer effect on gene expression is thought to be additive (Hay et al., 2016, Will et al., 2017).”
MethodSelf-citationSuper-enhancers: drivers of cells’ identities and cells’ debacles
Lavaud, M., Tesfaye, R. A., Lassous, L., Royer, B. B.-L., Baud’huin, M., Verrecchia, F., Lamoureux, F., Georges, S., & Ory, B. (2024) · Epigenomics · doi:10.2217/epi-2023-0409 · Cited by 15
Zhang, Y., Chen, K., Tang, S. C., Cai, Y., Niibori-Nambu, A., See, Y. X., Fu, C., Raju, A., Lebeau, B., Ling, Z., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01391-7 · Cited by 16
Scalable in vitro production of defined mouse erythroblasts
Francis, H. S., Harrold, C. L., Beagrie, R. A., King, A. J., Gosden, M. E., Blayney, J., Jeziorska, D. M., Babbs, C., Higgs, D. R., & Kassouf, M. T. (2022) · PLoS ONE · doi:10.1371/journal.pone.0261950 · Cited by 12
“Deletion of one of the major enhancers of the adult α -globin genes, R1, reduces the expression of alpha globin by 40% in definitive erythroid cells [20]; the same effect is seen in E10.”
InfluentialSelf-citationMatthews, B. J., Melia, T., & Waxman, D. J. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009588 · Cited by 12
Decoding transcriptional states in cancer
Wouters, J., Atak, Z. K., & Aerts, S. (2017) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2017.01.003 · Cited by 13
ATR-16 syndrome: mechanisms linking monosomy to phenotype
Babbs, C., Brown, J. M., Horsley, S. W., Slater, J., Maifoshie, E., Kumar, S., Ooijevaar, P., Kriek, M., Dixon‐McIver, A., Harteveld, C. L., et al. (2020) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2019-106528 · Cited by 12
Self-citationLi, Z., Shang, X., Luo, S., et al. (2020) · Molecular Genetics and Genomics · doi:10.1007/s00438-019-01637-w · Cited by 12
Fong, S., & Capra, J. A. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab138 · Cited by 12
The non-coding genome in genetic brain disorders: new targets for therapy?
Salsench, E. M., Karkala, F., Lanko, K., & Barakat, T. S. (2021) · Essays in Biochemistry · doi:10.1042/ebc20200121 · Cited by 11
Multiplex profiling of developmental enhancers with quantitative, single-cell expression reportersPreprint
Lalanne, J.-B., Regalado, S. G., Domcke, S., Calderon, D., Martin, B., Li, T., Suiter, C. C., Lee, C., Trapnell, C., & Shendure, J. (2022) · bioRxiv · doi:10.1101/2022.12.10.519236 · Cited by 14
Engineering structural variants to interrogate genome function
Koeppel, J., Weller, J., Vanderstichele, T., & Parts, L. (2024) · Nature Genetics · doi:10.1038/s41588-024-01981-7 · Cited by 12
“In the initial work, homologous recombination was used to delete each of the five regulatory elements individually or in two pairwise combinations, which led to the proposal of an additive model of their action 29 .”
A Sox2 enhancer cluster regulates region-specific neural fates from mouse embryonic stem cells
Tobias, I. C., Moorthy, S. D., Shchuka, V. M., Langroudi, L., Cherednychenko, M., Gillespie, Z. E., Duncan, A. G., Tian, R., Gajewska, N. A., Roberto, R. B. D., et al. (2025) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkaf012 · Cited by 13
“However, a single gene can be regulated by multiple enhancers active in different cellular contexts or by redundant enhancers with some degree of overlapping spatiotemporal function (Hay et al .”
Natural and Experimental Rewiring of Gene Regulatory Regions
Downes, D. J., & Hughes, J. R. (2022) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-112921-010715 · Cited by 12
Self-citationBadat, M., Davies, J. O. J., Fisher, C. A., Downes, D. J., Rose, A. M., Glenthøj, A. B., van Beers, E. J., Harteveld, C. L., & Higgs, D. R. (2020) · Blood · doi:10.1182/blood.2020006680 · Cited by 11
Self-citationCTCF fences make good neighbours
Krivega, I. V., & Dean, A. (2017) · Nature Cell Biology · doi:10.1038/ncb3584 · Cited by 11
Gillespie, M. A. K., Palii, C. G., Sánchez‐Taltavull, D., Shannon, P. T., Longabaugh, W. J. R., Downes, D. J., Sivaraman, K., Hughes, J. R., Price, N. D., Perkins, T. J., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/812123 · Cited by 12
Self-citationStolper, R. J., Tsang, F. H., Georgiades, E., Hansen, L. L. P., Downes, D. J., Harrold, C. L., Hughes, J. R., Beagrie, R. A., Davies, B., Kassouf, M. T., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.07.556660 · Cited by 11
“For normalisation, peaks were called on a subset of ChIP samples with Lanceotron(Hentges, Sergeant et al. 2021), using model wide- and-deep_jan-2021, on bigWig files generated using bamCoverage (part of deeptools 3.4.3, (Ramírez et al. 2016)) with extendReads (default), binsize 1 and normalisation…”
MethodInfluentialSelf-citationThe characteristics of CTCF binding sequences contribute to enhancer blocking activity
Tsang, F. H., Stolper, R. J., Hanifi, M., Cornell, L., Francis, H. S., Davies, B., Higgs, D. R., & Kassouf, M. T. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae666 · Cited by 10
“The alpha-globin enhancers and genes are located within a ∼ 65kb sub-TAD (topologically associating domain) that is largely delimited by an array of con-vergently oriented CTCF binding sites ( 31 , 42 , 43 ) (Figure 1 A).”
BackgroundSelf-citationZhu, X., Huang, Q., Luo, J., Kong, D., & Zhang, Y. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.02.028 · Cited by 12
“In regulatory networks, each enhancer is independent and functions in a synergistic manner [25,26].”
Bagheri, H., Friedman, H. C., Siminovitch, K. A., & Peterson, A. C. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008752 · Cited by 10
Improving ATAC-seq Data Analysis with AIAP, a Quality Control and Integrative Analysis PackagePreprint
Liu, S., Li, D., Lyu, C., Gontarz, P. M., Miao, B., Madden, P. A. F., Wang, T., & Zhang, B. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/686808 · Cited by 10
“The uniquely aligned PE reads have been used to call open chromatin peaks after alignment in many studies[26-32].”
MethodDissecting regulatory syntax in human development with scalable multiomics and deep learningPreprint
Liu, B. B., Jessa, S., Kim, S. H., Ng, Y. T., Higashino, S. I., Marinov, G. K., Chen, D. C., Parks, B. E., Li, L., Nguyen, T. C., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.30.651381 · Cited by 10
Self-citationShao, L., Yu, H., Wang, M., Chen, L., Ji, B., Wu, T. Q., Teng, X., Su, M., Han, X., Shi, W., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06915-z · Cited by 9
Mammalian genome writing: Unlocking new length scales for genome engineering
Pinglay, S., Atwater, J. T., Brosh, R., Shendure, J., Maurano, M. T., & Boeke, J. D. (2026) · Cell · doi:10.1016/j.cell.2025.12.034 · Cited by 11
An encyclopedia of human enhancer–gene regulatory interactions
Gschwind, A. R., Mualim, K. S., Karbalayghareh, A., Sheth, M. U., Dey, K. K., Jagoda, E., Nurtdinov, R., Xi, W., Tan, A. S., Galante, J., et al. (2026) · Nature · doi:10.1038/s41586-026-10781-4 · Cited by 161
Functional genomic assays to annotate enhancer–promoter interactions genome wide
Leung, A. K.-Y., Li, Y., & Yu, H. (2022) · Human Molecular Genetics · doi:10.1093/hmg/ddac204 · Cited by 9
“Multiple enhancer targets have been successfully identified with this method (68–75), including enhancers of globin genes (69,75), CDKN1A (70) and Myc (76).”
MethodBenton, M. L., Ruderfer, D. M., & Capra, J. A. (2023) · Genome Biology and Evolution · doi:10.1093/gbe/evad126 · Cited by 9
From Genotype to Phenotype: How Enhancers Control Gene Expression and Cell Identity in Hematopoiesis
Mulet‐Lazaro, R., & Delwel, R. (2023) · HemaSphere · doi:10.1097/hs9.0000000000000969 · Cited by 11
“200,201 Dissection by genetic manipulation revealed that disruption of constituent enhancers enriched in chromatin interactions (hub enhancers) destabilizes the whole SE, suggesting a hierarchical model of organization.”
BackgroundSuper-Enhancers Dysregulations in Hematological Malignancies
Belloucif, Y., & Lobry, C. (2022) · Cells · doi:10.3390/cells11020196 · Cited by 10
“Interestingly, they found that none of the five enhancers were significantly required to control the expression of any of the globin genes, strongly supporting the additive hypothesis [49].”
BackgroundCico, A., Andrieu‐Soler, C., & Soler, É. (2016) · FEBS Letters · doi:10.1002/1873-3468.12424 · Cited by 11
Zhou, J., Guruvayurappan, K., Toneyan, S., Chen, H. V., Chen, A. R., Koo, P. K., & McVicker, G. (2024) · Cell Genomics · doi:10.1016/j.xgen.2024.100672 · Cited by 11
“7 In addition, a study that systematically deleted three constituent enhancers of a super-enhancer for Wap in mice found differences in the magnitudes of effect that each enhancer had onthe target gene and no evidenceof synergy between the enhancers, with all three enhancers necessary to induce…”
BackgroundDNA G-quadruplex structures act as functional elements in α- and β-globin enhancers
Doyle, C., Herka, K., Flynn, S. M., Melidis, L., Dhir, S., Schoenfelder, S., Tannahill, D., & Balasubramanian, S. (2025) · Genome biology · doi:10.1186/s13059-025-03627-1 · Cited by 10
“For the α-globin LCR, individual enhancers are thought to act as independent regulatory units [31], with HS-40 (also known as multispecies conserved regulatory sequence 2, MCS-R2) regulating ~50% of target gene expression [32].”
Wu, C., & Huang, J. (2024) · BMC Genomics · doi:10.1186/s12864-024-10408-w · Cited by 8
Erythroid Cell Research: 3D Chromatin, Transcription Factors and Beyond
Andrieu‐Soler, C., & Soler, É. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116149 · Cited by 8
“erythroid cells during terminal differentiation [13,14].”
Translating non-coding genetic associations into a better understanding of immune-mediated disease
Stankey, C. T., & Lee, J. C. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.049790 · Cited by 9
“Studies that have deleted or mutated component enhancers within super-enhancer loci have found that the effects of such disruption range from mild decreases to near-complete ablation of target gene expression (Hay et al., 2016; Moorthy et al., 2017; Shin et al., 2016).”
BackgroundLin, H., Ye, X., Chen, W., Hong, D., Liu, L., Chen, F., Sun, N., Ye, K., Hong, J., Zhang, Y., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkae1323 · Cited by 7
A Comparative Analysis of Super-Enhancers and Broad H3K4me3 Domains in Pig, Human, and Mouse Tissues
Peng, Y., Kang, H., Luo, J., & Zhang, Y. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.701049 · Cited by 7
Smith, S. S., Chu, D. B., Qu, T., Aggleton, J. A., & Schneider, R. A. (2022) · eLife · doi:10.7554/elife.66005 · Cited by 7
“The globin genes are a well-studied case ( Pace and Makala, 2012 ), although these also appear to rely on distal enhancers for their regulation ( Hay et al., 2016 ).”
Review: Enhancers in Autoimmune Arthritis: Implications and Therapeutic Potential
Peeters, J. G. C., Vastert, S. J., van Wijk, F., & van Loosdregt, J. (2017) · Arthritis & Rheumatology · doi:10.1002/art.40194 · Cited by 7
CREAM: Clustering of genomic REgions Analysis MethodPreprint
Tonekaboni, S. A. M., Mazrooei, P., Kofia, V., Haibe‐Kains, B., & Lupien, M. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/222562 · Cited by 8
Zhu, I., & Landsman, D. (2023) · Genome Research · doi:10.1101/gr.278130.123 · Cited by 9
Resolution of a human super-enhancer by targeted genome randomisationPreprint
Koeppel, J., Murat, P., Girling, G., Peets, E. M., Gouley, M., Rebernig, V., Maheshwari, A., Hepkema, J., Weller, J., Jebaraj, J. H. J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.14.632548 · Cited by 7
Configuring the Code: Enhancer-Promoter Arrangement and Transcriptional Regulation
Buitrago, N., Vidal, J. A., & Lim, B. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169417 · Cited by 7
Genetic and Epigenetic Dysregulation of Transcriptional Enhancers in Cancer
Botten, G. A., & Xu, J. (2024) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-060324-114306 · Cited by 7
MYC as a driver of stochastic chromatin networks: implications for the fitness of cancer cells
Sumida, N., Sifakis, E. G., Kiani, N. A., Ronnegren, A. L., Scholz, B. A., Vestlund, J., Gómez-Cabrero, D., Tegner, J. N., Göndör, A., & OHLSSON, R. I. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa817 · Cited by 6
Building integrative functional maps of gene regulation
Xu, J., Pratt, H., Moore, J. E., Gerstein, M., & Weng, Z. (2022) · Human Molecular Genetics · doi:10.1093/hmg/ddac195 · Cited by 6
Facilitators may represent a new class of regulatory elements
Kassouf, M. T., Rampasekova, A., & Higgs, D. R. (2026) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2026.102444 · Cited by 6
Self-citationNon-coding variants impact cis-regulatory coordination in a cell type-specific manner
Pushkarev, O., van Mierlo, G., Kribelbauer, J. F., Saelens, W., Gardeux, V., & Deplancke, B. (2024) · Genome biology · doi:10.1186/s13059-024-03333-4 · Cited by 8
“8 Hay, D. et al. (2016) Genetic dissection of the α-globin super-enhancer in vivo.”
BackgroundApplication Strategies of Super-Enhancer RNA in Cardiovascular Diseases
He, Y., Cai, Y., Cao, Y., Wang, Y., Wang, J., & Ding, H. (2025) · Biomedicines · doi:10.3390/biomedicines13010117 · Cited by 5
“(5) SEs are associated with a high density of RNA polymerase II, which enables the transcription of large amounts of SE-associated RNA [25–27].”
The Th1 cell regulatory circuitry is largely conserved between human and mouse
Henderson, S. R., Pullabhatla, V., Hertweck, A., de Rinaldis, E., Herrero, J., Lord, G. M., & Jenner, R. G. (2021) · Life Science Alliance · doi:10.26508/lsa.202101075 · Cited by 5
Multimodal single cell analysis infers widespread enhancer co-activity in a lymphoblastoid cell line
Ziyani, C., Delaneau, O., & Ribeiro, D. M. (2023) · Communications Biology · doi:10.1038/s42003-023-04954-4 · Cited by 4
Rapid and efficient enhancer cloning and in vivo screening using the developing chick embryo
Williams, R. M., & Sauka‐Spengler, T. (2021) · STAR Protocols · doi:10.1016/j.xpro.2021.100507 · Cited by 5
Self-citationNo Need to Stick Together to Be Connected: Multiple Types of Enhancers’ Networking
Vitale, E., Gugnoni, M., & Ciarrocchi, A. (2021) · Cancers · doi:10.3390/cancers13205201 · Cited by 5
“Supportive ENHs significantly contribute to gene expression only in the presence of the functional predominant ENH [20,21,78,90,91].”
BackgroundHaemolysis in sickle cell anaemia: effects of polymorphisms in α‐globin gene regulatory elements
Milton, J. N., Mohammed, E. S. E., & Steinberg, M. H. (2019) · British Journal of Haematology · doi:10.1111/bjh.15852 · Cited by 5
Sumida, N., Sifakis, E. G., Scholz, B. A., Fernandez-Woodbridge, A., Kiani, N. A., Gómez-Cabrero, D., Svensson, J. P., Tegner, J. N., Göndör, A., & OHLSSON, R. I. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/286583 · Cited by 5
“The arrangement of large domains with enhancing activities, the so-called super-enhancers has been proposed to reduce transcriptional noise and buffer against environmental perturbations in order to robustly maintain the differentiated phenotype (Hnisz et al. 2013; Hay et al. 2016).”
BackgroundMultipartite super-enhancers function in an orientation-dependent mannerPreprint
Kassouf, M. T., Francis, H. S., Gosden, M. E., Suciu, M., Downes, D. J., Harrold, C. L., Larke, M., Oudelaar, A. M., Cornell, L., Blayney, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.14.499999 · Cited by 6
Self-citationZhou, J., Guruvayurappan, K., Toneyan, S., Chen, H. V., Chen, A. R., Koo, P. K., & McVicker, G. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.26.538501 · Cited by 5
Super enhancers as key drivers of gene regulatory networks in normal and malignant hematopoiesis
Cheng, Y., Pei, G., Zhang, H., Hou, Y., Sun, L., Xu, H., Lv, Y., & Wu, X. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1674470 · Cited by 5
The Making of a cDC1 : Precision Programming of Progenitor Potential
Murphy, T. L., & MURPHY, K. M. M. (2025) · Immunological Reviews · doi:10.1111/imr.70081 · Cited by 8
Extensive enhancer crosstalk controls PPARG2 activation during adipogenesis
Cetnarowska, A., Hyldahl, M., Nygård, M., Dashti, H., Hansen, B. M., Holm, L. K., Madsen, K., Madsen, M. S., Shukla, V., Mitchell, E. D., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70401-7 · Cited by 4
“Early studies indicated that enhancers cooperate in an additive manner to activate gene expression 20 ; however, more recent studies have demonstrated context-and distance-dependent synergy between some enhancers 17,23,24 , indicating that enhancers could affect the activity of each other.”
Large-scale analysis of the integration of enhancer-enhancer signals by promoters
Martinez-Ara, M., Comoglio, F., & van Steensel, B. (2024) · eLife · doi:10.7554/elife.91994.3 · Cited by 5
Shaping gene expression and its evolution by chromatin architecture and enhancer activity
Mañes-García, J., Marco-Ferreres, R., & Beccari, L. L. (2024) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2024.01.001 · Cited by 4
Felder, A.-K., Tjalsma, S. J. D., Verhagen, H. J. M. P., Majied, R., Verstegen, M. J. A. M., Verheul, T. C. J., van Haren, J., Mohnani, R., Gremmen, R., Krijger, P. H. L., et al. (2025) · Blood · doi:10.1182/blood.2024028128 · Cited by 8
Sethi, S., Vorontsov, I. E., Kulakovskiy, I. V., Greenaway, S., Williams, J. A., Makeev, V. J., Brown, S. D. M., Simon, M. M., & Mallon, A. (2020) · BMC Genomics · doi:10.1186/s12864-020-07109-5 · Cited by 4
Super-enhancers: Implications in gastric cancer
Huang, Y., Huo, Y., Huang, L., Zhang, L., Zheng, Y., Zhang, N., & Yang, M. W. O. (2024) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2024.108489 · Cited by 4
Vadolas, J., Nualkaew, T., Voon, H. P. J., Vilcassim, S., & Grigoriadis, G. (2024) · HemaSphere · doi:10.1002/hem3.78 · Cited by 5
“In – 24 Recent three ‐ dimensional chromatin conformation studies of the mouse α ‐ globin locus have delineated FIGURE 1 Schematic presentation of the human α ‐ globin gene cluster depicting functional and topological regulators of α ‐ globin gene expression.”
BackgroundEpigenetic Targeting of Aberrant Transcriptional Modulation in Pancreatic Cancer
Hamdan, F. H., & Johnsen, S. A. (2018) · Epigenomes · doi:10.3390/epigenomes2020008 · Cited by 4
“However, this is not usually the case given that, as previously discussed, BET inhibition has the ability to turn off certain BET-dependent super enhancers but deletion of individual components of “super enhancers” does not equally impair the activation of the target gene [56,57,95,108,109].”
BackgroundThe assembly and functions of multiway enhancer–promoter hubs
Islam, Z., Shigvan, S., Singh, A., & Notani, D. (2026) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2026.102446 · Cited by 3
Kyrchanova, O., Kudryashova, K. S., Ibragimov, A. N., Dubrovskaya, V. A., Schedl, P. D., & Georgiev, P. G. (2025) · Development · doi:10.1242/dev.205051 · Cited by 3
Nanoscale nuclear environments, fine-scale 3D genome organization and transcription regulation
Li, J., & Pertsinidis, A. (2022) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2022.100436 · Cited by 3
CRISPR Activator Approaches to Study Endogenous Androglobin Gene Regulation
Koay, T. W., Schödel, J., & Hoogewijs, D. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-3080-8_11 · Cited by 3
Huang, S., Reed, C., Ilsley, M. D., Magor, G. W., Tallack, M. R., Landsberg, M. J., Mitchell, H., Gillinder, K. R., & Perkins, A. C. (2024) · Nature Communications · doi:10.1038/s41467-024-50579-4 · Cited by 3
Multilayered Mechanisms for Long-range Regulatory Interactions in Eukaryotic Transcription
Fukaya, T. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169311 · Cited by 3
He, Y., Luo, J., Chen, Y., Zhou, X., Yu, S., Jin, L., Xiao, X., Jia, S., & Liu, Q. (2017) · Molecular Genetics and Genomics · doi:10.1007/s00438-017-1377-2 · Cited by 3
Classification of different types of estrogen receptor alpha binding sites in MCF-7 cells
Bojcsuk, D., & Bálint, B. L. (2019) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2019.04.016 · Cited by 3
A Cambrian origin for globin gene regulation.
Hardison, R. C. (2020) · PubMed Central · doi:10.1182/blood.2020006649 · Cited by 3
chromMAGMA: regulatory element-centric interrogation of risk variants
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) · Life Science Alliance · doi:10.26508/lsa.202201446 · Cited by 4
“This step simplifies the biological complexity of multiple REs influencing a gene in an additive (Hay et al. 2016; Kawakami et al. 2021), or sometimes hierarchal manner (Shin et al.”
BackgroundModelling erythropoiesis in congenital dyserythropoietic anaemia type I (CDA-I)Preprint
Scott, C., Downes, D. J., Brown, J. M., Babbs, C., Olijnik, A.-A., Gosden, M. E., Beagrie, R. A., Schweßinger, R., Fisher, C. A., Rose, A. M., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/744367 · Cited by 3
Self-citationTargeted high-resolution chromosome conformation capture at genome-wide scalePreprint
Downes, D. J., Gosden, M. E., Telenius, J. M., Carpenter, S. J., Nußbaum, L., Ornellas, S. D., Sergeant, M. J., Eijsbouts, C. Q., Schweßinger, R., Kerry, J., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.02.953745 · Cited by 3
Self-citationSuper-silencers regulated by chromatin interactions control apoptotic genesPreprint
Zhang, Y., Chen, K., Cai, Y., Niibori-Nambu, A., See, Y. X., Fu, C., Raju, A., Lakshmanan, M., Osato, M., Tergaonkar, V., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.17.476559 · Cited by 3
“Similarly, Hay et al (Hay et al., 2016) interrogated the α-globin SE in vivo.”
BackgroundAncient genomic linkage couples 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) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.25.558944 · Cited by 2
Self-citationLoubière, V., de Almeida, B. P., Pagani, M., & Stark, A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.10.561770 · Cited by 3
Large-scale analysis of the integration of enhancer-enhancer signals by promotersPreprint
Martinez-Ara, M., Comoglio, F., & van Steensel, B. (2023) · eLife · doi:10.7554/elife.91994.1 · Cited by 3
Felder, A.-K., Tjalsma, S. J. D., Verhagen, H. J. M. P., Majied, R., Verstegen, M. J. A. M., Verheul, T. C. J., Mohnani, R., Gremmen, R., Krijger, P. H. L., Philipsen, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.13.632719 · Cited by 3
Revisiting models of enhancer–promoter communication in gene regulationPreprint
Barshad, G., & Danko, C. G. (2025) · Genome Research · doi:10.1101/gr.278389.123 · Cited by 4
“…numerous examples in which enhancers regulate gene expression from long genomic distances ( ∼ 10 – 100 kb) and are occasionally found >1 Mb away from the target promoter (Lettice et al. 2003; Spitz et al. 2003; Antonellis et al. 2006; Ghiasvand et al. 2011; Hay et al. 2016; Gasperini et al. 2019).”
MYB represses ζ-globin expression through upregulating ETO2
Dong, Z., Ye, Y., Zhang, W., Luo, H., Li, J., Zhang, Q., Zhang, X., Guo, X., & Xu, X. (2024) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2024239 · Cited by 2
“The α - like globin locus in both humans and mice harbors three functional genes, including an embryonic ζ - globin gene and two duplicated adult α - globin genes [11].”
Chromatin spatial analysis by METALoci unveils sex-determining 3D regulatory hubs
Mota-Gómez, I., Rodríguez, J. A., Dupont, S. M., Hurtado, A., Cadenas, V., Zuber, L., Maceda, I., Lao, Ó., Jedamzick, J., Kühn, R., et al. (2026) · Yearbook of pediatric endocrinology · doi:10.1038/s41594-026-01749-z · Cited by 16
Molecular co-accessibility identifies coordinated regulation between distant cis-regulatory elements
Boulanger, M., Chatsirisupachai, K., Badayeva, Y., Snajder, R., Bonder, M. J., Lapouge, K., Remans, K., & Krebs, A. R. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.07.020 · Cited by 5
Chromatin architecture and topology in pluripotent stem cells
Platania, A., & Sexton, T. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-814085-7.00004-0 · Cited by 3
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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