Biology:Super-enhancer

From HandWiki

A super-enhancer, illustrated in the lower panel of the Figure, is a region of the mammalian genome comprising multiple typical enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity,[1][2][3] or of genes involved in cancer.[4] Because super-enhancers frequently occur near genes important for controlling and defining cell identity, they may be used to quickly identify key nodes regulating cell identity.[3][5] Super-enhancers are also central to mediating dysregulation of signaling pathways and promoting cancer cell growth.[4][6] Super-enhancers differ from typical enhancers, however, in that they are strongly dependent on additional specialized proteins that create and maintain their formation, including BRD4 (shown in the lower panel of Figure) and co-factors including p300.[7]

Enhancers have several quantifiable traits that have a range of values, and these traits are generally elevated at super-enhancers. Super-enhancers are bound by higher levels of transcription-regulating proteins and are associated with genes that are more highly expressed.[1][8][9][10] Expression of genes associated with super-enhancers is particularly sensitive to perturbations, which may facilitate cell state transitions or explain sensitivity of super-enhancer–associated genes to small molecules that target transcription.[1][8][9][11][12]

Frequency of super-enhancers

In many cell types, only a minority of activated enhancers are located in Super-Enhancers (SEs). For specialized tissue, such as skeletal muscle, a reduced number of genes are expressed and a low number of specialized and activated super-enhancers are found. In human skeletal muscle, there are nine identified types of cells. On average, the number of expressed genes in these nine cell types is 1,331.[13] There are also about 22 super-enhancers specific to skeletal muscle cells among the nine types of skeletal muscle cells, indicating that specialized super-enhancers in these cells are about 1.7% of the number of typical enhancers (TEs).[14] In immune-system B cells, a study identified 140 SEs and 4,290 TEs in non-stimulated B cells (SEs were 3.2% of activated transcription areas). In stimulated B cells SEs were 3.6% of activated transcription areas.[15] Similarly, in mouse embryonic stem cells, 231 SEs were found, compared to 8,794 TEs, with SEs comprising 2.6% of activated chromatin regions.[16] A study of neural stem cells found 445 SEs and 9436 TEs, so that SEs were 4.7% of active enhancer regions.[17]

Formation of super-enhancers

Hundreds of thousands of sites in the human genome can potentially act as enhancers. In one large 2020 study, 78 different types of human cells were examined for links between activated enhancers and genes coding for messenger RNA to produce gene products. Distributed among the 78 types of cells there were a total of 449,627 activated enhancers linked to 17,643 protein-coding genes.[18] With this large number of potentially active enhancers, there are some genome regions with a cluster of enhancers that, when all are activated they can all loop to the same promoter and produce a super-enhancer, driving a gene to have very high messenger RNA output.

One well-studied gene, MYC, has amplified expression in as many as 70% of all cancers.[19] While about 28% of its over-expressions are due to genetic focal amplifications or translocations,[20] the majority of cases of over-expression of MYC are due to activated super-enhancers.[21] There are more than 10 different super-enhancers that can cause MYC over-expression. For each of 4 tumor types of cells grown in culture (HCT-116, MCF7, K562 and Jurkat) there were three to five super-enhancers specific to each tumor cell type.

The upper image shows chromatin and the lower image shows chromatin with nucleosomal eviction.

In one 2013 study,[22] the length of typical enhancers was found to be about 700 base pairs while in the case of super-enhancers the length was about 9,000 base pairs (encompassing multiple single enhancers). A later study, in 2020, indicated that typical enhancers were about 200 nucleotides long and that there may be as many as 3.6 million potentially active enhancers occupying 21.55% of the human genome.[23]

In the nucleus of mammalian cells, almost all the DNA is wrapped around regularly spaced protein complexes, called nucleosomes (see top panel in Figure "Chromatin").[24] The protein complexes are composed of 4 pairs of histones, H2A, H2B, H3 and H4. The DNA plus these protein complexes is called chromatin (see Figure illustrating chromatin). Enhancer regions, as described above, are several hundred nucleotides long. To be activated, the enhancer region must have the nucleosomes evicted from the DNA so that the multiple transcription factors that bind to that enhancer DNA would have access to their binding sites (see bottom panel in Figure "Chromatin"). (To be an active enhancer, more than 10 different binding sites must be occupied by different transcription factors in the enhancer.[23])

Nucleosome at an enhancer region of DNA. Enhancer nucleosomes can be identified by having histone 3 mono-methylated at lysine (K) 4 and acetylated at lysine (K) 27 (the single-letter abbreviation for lysine is K).[25] To free the DNA from the nucleosome, so that transcription factors can bind to their binding sites, histone 3 would also be acetylated at lysine 122 as shown in this figure. Acetylation of histone 3 at lysine 122 leads to eviction of the nucleosome from chromatin. Eviction of nucleosomes at enhancers is an early step necessary for formation of a super-enhancer

In eviction of nucleosomes from enhancer DNA, a pioneer transcription factor first loosens up the attachment of DNA to the nucleosome of an enhancer region. For instance, one transcription factor that does this is the pioneer transcription factor NF-κB.[26] Five steps follow this:

  1. NF-κB is acetylated by p300/CBP.
  2. Acetylated NF-κB recruits a specific histone acetyltransferase enzyme, BRD4.[27]
  3. BRD4 acetylates histone 3 at histone 3 lysine 122 (see Figure "Nucleosome at enhancer with H3K122 acetylated").
  4. When histone 3 lysine 122 is acetylated the nucleosome is evicted from the enhancer sequence.[28]
  5. Opening up the enhancer DNA allows binding of the other transcription factors needed to form an activated enhancer.

Presumably, when the activating signal for NF-κB is very strong, much more NF-κB is activated, and then greatly increased NF-κB can start the process of activating multiple nearby enhancers at the same time, forming a super-enhancer.

Super-enhancers promote high levels of transcription

As described above, in forming a super-enhancer, BRD4 is complexed with NF-kB. This complex also recruits and forms a further complex with cyclin T1 and Cdk9. Cyclin T1/Cdk9 is also known as P-TEFb. P-TEFb acts as a kinase that phosphorylates RNA polymerase II (RNAP II), which then activates (in conjunction with the Mediator complex described below) the polymerase on the promoter of a gene to initiate transcription and to continue transcription (instead of pausing).[29]

The transcription factors, bound to their sites on each enhancer within the super-enhancer, recruit the Mediator complex between each enhancer and the RNA polymerase II that will initiate transcription of the gene to be actively transcribed (see Figure at top of article that illustrates a super-enhancer). The Mediator complex in humans is 1.4 MDa in size and includes 26 sub-units.[30] The tail modules of the Mediator complex protein sub-units interact with the activation domains of transcription factors bound at enhancers and the head and middle modules interact with the pre-initiation complex (PIC) at gene promoters.[31] The Mediator complex, when certain sub-units are phosphorylated and up-activated by particular cyclin-dependent kinases (Cdk8, Cdk9, Cdk19, etc.), will then promote higher levels of transcription.

History

The regulation of transcription by enhancers has been studied since the 1980s.[32][33][34][35][36] Large or multi-component transcription regulators with a range of mechanistic properties, including locus control regions, clustered open regulatory elements, and transcription initiation platforms, were observed shortly thereafter.[37][38][39][40] More recent research has suggested that these different categories of regulatory elements may represent subtypes of super-enhancer.[3][41]

In 2013, two labs identified large enhancers near several genes especially important for establishing cell identities. While Richard A. Young and colleagues identified super-enhancers, Francis Collins and colleagues identified stretch enhancers.[1][2] Both super-enhancers and stretch enhancers are clusters of enhancers that control cell-specific genes and may be largely synonymous.[2][42]

As currently defined, the term "super-enhancer" was introduced by Young's lab to describe regions identified in mouse embryonic stem cells (ESCs).[1] These particularly large, potent enhancer regions were found to control the genes that establish the embryonic stem cell identity, including Oct-4, Sox2, Nanog, Klf4, and Esrrb. Perturbation of the super-enhancers associated with these genes showed a range of effects on their target genes' expression.[42] Super-enhancers have been since identified near cell identity-regulators in a range of mouse and human tissues.[2][3][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][excessive citations]

Function

The enhancers comprising super-enhancers share the functions of enhancers, including binding transcription factor proteins, looping to target genes, and activating transcription.[1][3][41][42] Three notable traits of enhancers comprising super-enhancers are their clustering in genomic proximity, their exceptional signal of transcription-regulating proteins, and their high frequency of physical interaction with each other. Perturbing the DNA of enhancers comprising super-enhancers showed a range of effects on the expression of cell identity genes, suggesting a complex relationship between the constituent enhancers.[42] Super-enhancers separated by tens of megabases cluster in three-dimensions inside the nucleus of mouse embryonic stem cells.[60][61]

High levels of many transcription factors and co-factors are seen at super-enhancers (e.g., CDK7, BRD4, and Mediator).[1][3][8][9][11][12][41] This high concentration of transcription-regulating proteins suggests why their target genes tend to be more highly expressed than other classes of genes. However, housekeeping genes tend to be more highly expressed than super-enhancer—associated genes.[1]

Super-enhancers may have evolved at key cell identity genes to render the transcription of these genes responsive to an array of external cues.[42] The enhancers comprising a super-enhancer can each be responsive to different signals, which allows the transcription of a single gene to be regulated by multiple signaling pathways.[42] Pathways seen to regulate their target genes using super-enhancers include Wnt, TGFb, LIF, BDNF, and NOTCH.[42][62][63][64][65] The constituent enhancers of super-enhancers physically interact with each other and their target genes over a long range sequence-wise.[10][44][66] Super-enhancers that control the expression of major cell surface receptors with a crucial role in the function of a given cell lineage have also been defined. This is notably the case for B-lymphocytes, the survival, the activation and the differentiation of which rely on the expression of membrane-form immunoglobulins (Ig). The Ig heavy chain locus super-enhancer is a very large (25kb) cis-regulatory region, including multiple enhancers and controlling several major modifications of the locus (notably somatic hypermutation, class-switch recombination and locus suicide recombination).

Relevance to Disease

Mutations in super-enhancers have been noted in various diseases, including cancers, type 1 diabetes, Alzheimer's disease, lupus, rheumatoid arthritis, multiple sclerosis, systemic scleroderma, primary biliary cirrhosis, Crohn's disease, Graves disease, vitiligo, and atrial fibrillation.[2][3][9][47][54][57][67][68][69][70][71][excessive citations] A similar enrichment in disease-associated sequence variation has also been observed for stretch enhancers.[2]

Super-enhancers may play important roles in the misregulation of gene expression in cancer. During tumor development, tumor cells acquire super-enhancers at key oncogenes, which drive higher levels of transcription of these genes than in healthy cells.[3][8][66][67][72][73][74][75][76][77][78][79][80][81][excessive citations] Altered super-enhancer function is also induced by mutations of chromatin regulators.[82] Acquired super-enhancers may thus be biomarkers that could be useful for diagnosis and therapeutic intervention.[42]

Proteins enriched at super-enhancers include the targets of small molecules that target transcription-regulating proteins and have been deployed against cancers.[8][9][47][83] For instance, super-enhancers rely on exceptional amounts of CDK7, and, in cancer, multiple papers report the loss of expression of their target genes when cells are treated with the CDK7 inhibitor THZ1.[8][11][12][84] Similarly, super-enhancers are enriched in the target of the JQ1 small molecule, BRD4, so treatment with JQ1 causes exceptional losses in expression for super-enhancer—associated genes.[9]

Identification

Super-enhancers have been most commonly identified by locating genomic regions that are highly enriched in ChIP-Seq signal. ChIP-Seq experiments targeting master transcription factors and co-factors like Mediator or BRD4 have been used, but the most frequently used is H3K27ac-marked nucleosomes.[1][3][9][85][86][87] The program "ROSE" (Rank Ordering of Super-Enhancers) is commonly used to identify super-enhancers from ChIP-Seq data. This program stitches together previously identified enhancer regions and ranks these stitched enhancers by their ChIP-Seq signal.[1] The stitching distance selected to combine multiple individual enhancers into larger domains can vary. Because some markers of enhancer activity also are enriched in promoters, regions within promoters of genes can be disregarded. ROSE separates super-enhancers from typical enhancers by their exceptional enrichment in a mark of enhancer activity. Homer is another tool that can identify super-enhancers.[88]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 "Master transcription factors and mediator establish super-enhancers at key cell identity genes". Cell 153 (2): 307–19. April 2013. doi:10.1016/j.cell.2013.03.035. PMID 23582322. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants". Proceedings of the National Academy of Sciences of the United States of America 110 (44): 17921–6. October 2013. doi:10.1073/pnas.1317023110. PMID 24127591. Bibcode: 2013PNAS..11017921P. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "Super-enhancers in the control of cell identity and disease". Cell 155 (4): 934–47. November 2013. doi:10.1016/j.cell.2013.09.053. PMID 24119843. 
  4. ↑ 4.0 4.1 "Super-enhancer function and its application in cancer targeted therapy". npj Precis Oncol 4. 2020. doi:10.1038/s41698-020-0108-z. PMID 32128448. 
  5. ↑ "Models of human core transcriptional regulatory circuitries". Genome Research 26 (3): 385–96. March 2016. doi:10.1101/gr.197590.115. PMID 26843070. 
  6. ↑ "Super-enhancers complexes zoom in transcription in cancer". J Exp Clin Cancer Res 42 (1). July 2023. doi:10.1186/s13046-023-02763-5. PMID 37501079. 
  7. ↑ "Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer". Cancers (Basel) 14 (12): 2866. June 2022. doi:10.3390/cancers14122866. PMID 35740532. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "Targeting transcription regulation in cancer with a covalent CDK7 inhibitor". Nature 511 (7511): 616–20. July 2014. doi:10.1038/nature13393. PMID 25043025. PMC 4244910. Bibcode: 2014Natur.511..616K. https://dash.harvard.edu/bitstream/handle/1/13890593/4244910.pdf?sequence=1. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 "Selective inhibition of tumor oncogenes by disruption of super-enhancers". Cell 153 (2): 320–34. April 2013. doi:10.1016/j.cell.2013.03.036. PMID 23582323. 
  10. ↑ 10.0 10.1 "Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes". Cell 159 (2): 374–87. October 2014. doi:10.1016/j.cell.2014.09.030. PMID 25303531. 
  11. ↑ 11.0 11.1 11.2 "Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor". Cancer Cell 26 (6): 909–22. December 2014. doi:10.1016/j.ccell.2014.10.019. PMID 25490451. 
  12. ↑ 12.0 12.1 12.2 "CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer". Cell 159 (5): 1126–39. November 2014. doi:10.1016/j.cell.2014.10.024. PMID 25416950. 
  13. ↑ "Identification of underexplored mesenchymal and vascular-related cell populations in human skeletal muscle". Am J Physiol Cell Physiol 323 (6): C1586–C1600. December 2022. doi:10.1152/ajpcell.00364.2022. PMID 36342160. 
  14. ↑ "DNA Hypomethylation in Intragenic and Intergenic Enhancer Chromatin of Muscle-Specific Genes Usually Correlates with their Expression". Yale J Biol Med 89 (4): 441–455. December 2016. PMID 28018137. 
  15. ↑ "The Number of Transcription Factors at an Enhancer Determines Switch-like Gene Expression". Cell Rep 31 (9). June 2020. doi:10.1016/j.celrep.2020.107724. PMID 32492432. 
  16. ↑ "Master transcription factors and mediator establish super-enhancers at key cell identity genes". Cell 153 (2): 307–19. April 2013. doi:10.1016/j.cell.2013.03.035. PMID 23582322. 
  17. ↑ "Mediator complex interaction partners organize the transcriptional network that defines neural stem cells". Nat Commun 10 (1). June 2019. doi:10.1038/s41467-019-10502-8. PMID 31209209. Bibcode: 2019NatCo..10.2669Q. 
  18. ↑ "PEREGRINE: A genome-wide prediction of enhancer to gene relationships supported by experimental evidence". PLOS ONE 15 (12). 2020. doi:10.1371/journal.pone.0243791. PMID 33320871. Bibcode: 2020PLoSO..1543791M. 
  19. ↑ "MYC as a target for cancer treatment". Cancer Treat Rev 94. March 2021. doi:10.1016/j.ctrv.2021.102154. PMID 33524794. 
  20. ↑ "Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas". Cell Syst 6 (3): 282–300.e2. March 2018. doi:10.1016/j.cels.2018.03.003. PMID 29596783. 
  21. ↑ "Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism". Cell Rep 23 (2): 349–360. April 2018. doi:10.1016/j.celrep.2018.03.056. PMID 29641996. 
  22. ↑ "Super-enhancers in the control of cell identity and disease". Cell 155 (4): 934–47. November 2013. doi:10.1016/j.cell.2013.09.053. PMID 24119843. 
  23. ↑ 23.0 23.1 "A flexible repertoire of transcription factor binding sites and a diversity threshold determines enhancer activity in embryonic stem cells". Genome Res 31 (4): 564–575. April 2021. doi:10.1101/gr.272468.120. PMID 33712417. 
  24. ↑ "High-resolution mapping and characterization of open chromatin across the genome". Cell 132 (2): 311–22. January 2008. doi:10.1016/j.cell.2007.12.014. PMID 18243105. 
  25. ↑ "Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in whole-body function and human health". Mol Metab 53. November 2021. doi:10.1016/j.molmet.2021.101290. PMID 34252634. 
  26. ↑ "Transcription factor NF-κB unravels nucleosomes". Biochim Biophys Acta Gen Subj 1865 (9). September 2021. doi:10.1016/j.bbagen.2021.129934. PMID 34029641. 
  27. ↑ "Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA". Mol Cell Biol 29 (5): 1375–87. March 2009. doi:10.1128/MCB.01365-08. PMID 19103749. 
  28. ↑ "BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin". Nat Struct Mol Biol 23 (6): 540–8. June 2016. doi:10.1038/nsmb.3228. PMID 27159561. 
  29. ↑ "The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription". Mol Cell 19 (4): 523–34. August 2005. doi:10.1016/j.molcel.2005.06.027. PMID 16109376. 
  30. ↑ "The Mediator complex as a master regulator of transcription by RNA polymerase II". Nat Rev Mol Cell Biol 23 (11): 732–749. November 2022. doi:10.1038/s41580-022-00498-3. PMID 35725906. 
  31. ↑ "The Mediator complex regulates enhancer-promoter interactions". Nat Struct Mol Biol 30 (7): 991–1000. July 2023. doi:10.1038/s41594-023-01027-2. PMID 37430065. 
  32. ↑ "Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences". Cell 27 (2 Pt 1): 299–308. December 1981. doi:10.1016/0092-8674(81)90413-x. PMID 6277502. 
  33. ↑ "In vivo sequence requirements of the SV40 early promoter region". Nature 290 (5804): 304–10. March 1981. doi:10.1038/290304a0. PMID 6259538. Bibcode: 1981Natur.290..304B. 
  34. ↑ "Simian virus 40 tandem repeated sequences as an element of the early promoter". Proceedings of the National Academy of Sciences of the United States of America 78 (2): 943–7. February 1981. doi:10.1073/pnas.78.2.943. PMID 6262784. Bibcode: 1981PNAS...78..943G. 
  35. ↑ "Control of globin gene transcription". Annual Review of Cell Biology 6: 95–124. 1990. doi:10.1146/annurev.cb.06.110190.000523. PMID 2275826. https://zenodo.org/record/1234945. 
  36. ↑ "Resistance to intracellular infections: comparative genomic analysis of Nramp". Trends in Genetics 12 (6): 201–4. June 1996. doi:10.1016/0168-9525(96)30042-5. PMID 8928221. 
  37. ↑ "Locus control regions". Blood 100 (9): 3077–86. November 2002. doi:10.1182/blood-2002-04-1104. PMID 12384402. 
  38. ↑ "Position-independent, high-level expression of the human beta-globin gene in transgenic mice". Cell 51 (6): 975–85. December 1987. doi:10.1016/0092-8674(87)90584-8. PMID 3690667. http://repub.eur.nl/pub/2425. 
  39. ↑ "A map of open chromatin in human pancreatic islets". Nature Genetics 42 (3): 255–9. March 2010. doi:10.1038/ng.530. PMID 20118932. 
  40. ↑ "Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters". Nature Structural & Molecular Biology 18 (8): 956–63. August 2011. doi:10.1038/nsmb.2085. PMID 21765417. 
  41. ↑ 41.0 41.1 41.2 "What are super-enhancers?". Nature Genetics 47 (1): 8–12. January 2015. doi:10.1038/ng.3167. PMID 25547603. 
  42. ↑ 42.0 42.1 42.2 42.3 42.4 42.5 42.6 42.7 "Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers". Molecular Cell 58 (2): 362–70. April 2015. doi:10.1016/j.molcel.2015.02.014. PMID 25801169. 
  43. ↑ "Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes". Cell Reports 9 (1): 234–47. October 2014. doi:10.1016/j.celrep.2014.08.055. PMID 25263550. 
  44. ↑ 44.0 44.1 "3D Chromosome Regulatory Landscape of Human Pluripotent Cells". Cell Stem Cell 18 (2): 262–75. February 2016. doi:10.1016/j.stem.2015.11.007. PMID 26686465. 
  45. ↑ "Transcription factor binding dynamics during human ES cell differentiation". Nature 518 (7539): 344–9. February 2015. doi:10.1038/nature14233. PMID 25693565. Bibcode: 2015Natur.518..344T. 
  46. ↑ "Transcription factor co-occupied regions in the murine genome constitute T-helper-cell subtype-specific enhancers". European Journal of Immunology 45 (11): 3150–7. November 2015. doi:10.1002/eji.201545713. PMID 26300430. 
  47. ↑ 47.0 47.1 47.2 "Super-enhancers delineate disease-associated regulatory nodes in T cells". Nature 520 (7548): 558–62. April 2015. doi:10.1038/nature14154. PMID 25686607. Bibcode: 2015Natur.520..558V. 
  48. ↑ "Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma". Immunity 42 (1): 186–98. January 2015. doi:10.1016/j.immuni.2014.12.021. PMID 25607463. 
  49. ↑ "Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice". Nature 521 (7552): 366–70. May 2015. doi:10.1038/nature14289. PMID 25799994. Bibcode: 2015Natur.521..366A. 
  50. ↑ "Molecular architecture of transcription factor hotspots in early adipogenesis". Cell Reports 7 (5): 1434–42. June 2014. doi:10.1016/j.celrep.2014.04.043. PMID 24857666. 
  51. ↑ "Transcription factor cooperativity in early adipogenic hotspots and super-enhancers". Cell Reports 7 (5): 1443–55. June 2014. doi:10.1016/j.celrep.2014.04.042. PMID 24857652. 
  52. ↑ "Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice". Cell Metabolism 19 (4): 593–604. April 2014. doi:10.1016/j.cmet.2014.03.007. PMID 24703692. 
  53. ↑ "Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers". Genes & Development 29 (1): 7–22. January 2015. doi:10.1101/gad.250829.114. PMID 25504365. 
  54. ↑ 54.0 54.1 "Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants". Nature Genetics 46 (2): 136–43. February 2014. doi:10.1038/ng.2870. PMID 24413736. 
  55. ↑ "The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis". Nucleic Acids Research 43 (17): 8183–203. September 2015. doi:10.1093/nar/gkv688. PMID 26150426. 
  56. ↑ "Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte". Cell Reports 12 (2): 229–43. July 2015. doi:10.1016/j.celrep.2015.06.013. PMID 26146088. 
  57. ↑ 57.0 57.1 "Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization". Nucleic Acids Research 42 (20): 12570–84. November 2014. doi:10.1093/nar/gku1036. PMID 25352550. 
  58. ↑ "Environment drives selection and function of enhancers controlling tissue-specific macrophage identities". Cell 159 (6): 1327–40. December 2014. doi:10.1016/j.cell.2014.11.023. PMID 25480297. 
  59. ↑ "Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development". Nucleic Acids Research 43 (14): 6827–46. August 2015. doi:10.1093/nar/gkv589. PMID 26138486. 
  60. ↑ "Complex multi-enhancer contacts captured by Genome Architecture Mapping (GAM)". Nature 543 (7646): 519–524. March 2017. doi:10.1038/nature21411. PMID 28273065. Bibcode: 2017Natur.543..519B. 
  61. ↑ "Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus". Cell 174 (3): 744–757. June 2018. doi:10.1016/j.cell.2018.05.024. PMID 29887377. 
  62. ↑ "Stimulus-specific combinatorial functionality of neuronal c-fos enhancers". Nature Neuroscience 19 (1): 75–83. January 2016. doi:10.1038/nn.4170. PMID 26595656. 
  63. ↑ "A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia". Nature Medicine 20 (10): 1130–7. October 2014. doi:10.1038/nm.3665. PMID 25194570. 
  64. ↑ "NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers". Proceedings of the National Academy of Sciences of the United States of America 111 (2): 705–10. January 2014. doi:10.1073/pnas.1315023111. PMID 24374627. Bibcode: 2014PNAS..111..705W. 
  65. ↑ "Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia". Proceedings of the National Academy of Sciences of the United States of America 111 (46): E4946-53. November 2014. doi:10.1073/pnas.1407079111. PMID 25369933. Bibcode: 2014PNAS..111E4946Y. 
  66. ↑ 66.0 66.1 "Activation of proto-oncogenes by disruption of chromosome neighborhoods". Science 351 (6280): 1454–8. March 2016. doi:10.1126/science.aad9024. PMID 26940867. Bibcode: 2016Sci...351.1454H. 
  67. ↑ 67.0 67.1 "Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element". Science 346 (6215): 1373–7. December 2014. doi:10.1126/science.1259037. PMID 25394790. 
  68. ↑ "MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo". Proceedings of the National Academy of Sciences of the United States of America 113 (5): 1363–8. February 2016. doi:10.1073/pnas.1523482113. PMID 26787888. Bibcode: 2016PNAS..113.1363C. 
  69. ↑ "Genetic and epigenetic fine mapping of causal autoimmune disease variants". Nature 518 (7539): 337–43. February 2015. doi:10.1038/nature13835. PMID 25363779. Bibcode: 2015Natur.518..337F. 
  70. ↑ "Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes". Blood 124 (25): 3719–29. December 2014. doi:10.1182/blood-2014-06-582700. PMID 25331115. 
  71. ↑ "Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism". Nature 528 (7582): 418–21. December 2015. doi:10.1038/nature15540. PMID 26560027. Bibcode: 2015Natur.528..418O. 
  72. ↑ "Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma". Leukemia 28 (8): 1725–35. August 2014. doi:10.1038/leu.2014.70. PMID 24518206. 
  73. ↑ "An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma". Nature Genetics 48 (3): 265–72. March 2016. doi:10.1038/ng.3502. PMID 26829750. 
  74. ↑ "Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma". Nature 511 (7510): 428–34. July 2014. doi:10.1038/nature13379. PMID 25043047. Bibcode: 2014Natur.511..428N. 
  75. ↑ "Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients". Blood Cancer Journal 4 (3): e191. 14 March 2014. doi:10.1038/bcj.2014.13. PMID 24632883. 
  76. ↑ "A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia". Cell 157 (2): 369–81. April 2014. doi:10.1016/j.cell.2014.02.019. PMID 24703711. 
  77. ↑ "Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation". Genes & Development 27 (24): 2648–62. December 2013. doi:10.1101/gad.232710.113. PMID 24285714. 
  78. ↑ "Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma". Oncotarget 6 (30): 30178–93. October 2015. doi:10.18632/oncotarget.4903. PMID 26337082. 
  79. ↑ "Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1". Cell Reports 10 (7): 1082–95. February 2015. doi:10.1016/j.celrep.2015.01.042. PMID 25704812. 
  80. ↑ "Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape". Cell Reports 12 (8): 1300–13. August 2015. doi:10.1016/j.celrep.2015.06.078. PMID 26279576. 
  81. ↑ "Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers". Nature Genetics 48 (2): 176–82. February 2016. doi:10.1038/ng.3470. PMID 26656844. 
  82. ↑ "Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers". Nature Structural & Molecular Biology 25 (1): 61–72. January 2018. doi:10.1038/s41594-017-0007-3. PMID 29323272. 
  83. ↑ "Toward a BETter grasp of acetyl-lysine readers". Blood 125 (18): 2739–41. April 2015. doi:10.1182/blood-2015-03-630830. PMID 25931578. 
  84. ↑ "CDK7-dependent transcriptional addiction in triple-negative breast cancer". Cell 163 (1): 174–86. September 2015. doi:10.1016/j.cell.2015.08.063. PMID 26406377. 
  85. ↑ "SEA: a super-enhancer archive". Nucleic Acids Research 44 (D1): D172-9. January 2016. doi:10.1093/nar/gkv1243. PMID 26578594. 
  86. ↑ "dbSUPER: a database of super-enhancers in mouse and human genome". Nucleic Acids Research 44 (D1): D164-71. January 2016. doi:10.1093/nar/gkv1002. PMID 26438538. 
  87. ↑ "Histone H3K27ac separates active from poised enhancers and predicts developmental state". Proceedings of the National Academy of Sciences of the United States of America 107 (50): 21931–6. December 2010. doi:10.1073/pnas.1016071107. PMID 21106759. 
  88. ↑ "Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities". Molecular Cell 38 (4): 576–89. May 2010. doi:10.1016/j.molcel.2010.05.004. PMID 20513432. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Super-enhancer&oldid=4092560"