Super-enhancer

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The structures of a typical enhancer compared to a super-enhancer. Comparison typical enhancer and super enhancer.jpg
The structures of a typical enhancer compared to a super-enhancer.

Cell differentiation in multicellular organisms with different cell types is determined, in each cell type, by the expression of genes under the regulatory control of typical enhancers and super-enhancers.

Contents

A typical enhancer(TE), as illustrated in the top panel of the Figure, is a several hundred base pair region of DNA [1] [2] that can bind transcription factors to sequence motifs on the enhancer. The typical enhancer can come in proximity to its target gene through a large chromosome loop. A Mediator a complex (consisting of about 26 proteins in an interacting structure) communicates regulatory signals from the enhancer-located DNA-bound transcription factors to the promoter of a gene, regulating RNA transcription of the target gene.

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, [3] [4] [5] or of genes involved in cancer. [6] 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. [5] [7] Super-enhancers are also central to mediating dysregulation of signaling pathways and promoting cancer cell growth. [6] [8] 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. [9]

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. [3] [10] [11] [12] 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. [3] [10] [11] [13] [14]

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. [15] 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). [16] 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. [17] Similarly, in mouse embryonic stem cells, 231 SEs were found, compared to 8,794 TEs, with SEs comprising 2.6% of activated chromatin regions. [18] A study of neural stem cells found 445 SEs and 9436 TEs, so that SEs were 4.7% of active enhancer regions. [19]

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. [20] 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. [21] While about 28% of its over-expressions are due to genetic focal amplifications or translocations, [22] the majority of cases of over-expression of MYC are due to activated super-enhancers. [23] 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. Chromatin and chromatin with nucleosome eviction.jpg
The upper image shows chromatin and the lower image shows chromatin with nucleosomal eviction.

In one 2013 study, [24] 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. [25]

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"). [26] 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. [25] )

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). 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 Nucleosome at enhancer with H3K122 acetylated.jpg
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). 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-kB . [28] Five steps follow this: (1) NF-kB is acetylated by p300/CBP. (2) Acetylated NF-kB recruits a specific histone acetyltransferase enzyme, BRD4. [29] (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. [30] (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-kB is very strong, much more NF-kB is activated, and then greatly increased NF-kB 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). [31]

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. [32] 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. [33] The Mediator complex, when certain sub-units are phosphorylated and up-activated by particular cyclin-dependent kinases (Cdk8, Cdk9, Cdk19, etc.) it will then promote higher levels of transcription.

History

The regulation of transcription by enhancers has been studied since the 1980s. [34] [35] [36] [37] [38] 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. [39] [40] [41] [42] More recent research has suggested that these different categories of regulatory elements may represent subtypes of super-enhancer. [5] [43]

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. [3] [4] Both super-enhancers and stretch enhancers are clusters of enhancers that control cell-specific genes and may be largely synonymous. [4] [44]

As currently defined, the term “super-enhancer” was introduced by Young’s lab to describe regions identified in mouse embryonic stem cells (ESCs). [3] 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. [44] Super-enhancers have been since identified near cell identity-regulators in a range of mouse and human tissues. [4] [5] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61]

Function

The enhancers comprising super-enhancers share the functions of enhancers, including binding transcription factor proteins, looping to target genes, and activating transcription. [3] [5] [43] [44] 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. [44] Super-enhancers separated by tens of megabases cluster in three-dimensions inside the nucleus of mouse embryonic stem cells. [62] [63]

High levels of many transcription factors and co-factors are seen at super-enhancers (e.g., CDK7, BRD4, and Mediator). [3] [5] [10] [11] [13] [14] [43] 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. [3]

Super-enhancers may have evolved at key cell identity genes to render the transcription of these genes responsive to an array of external cues. [44] 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. [44] Pathways seen to regulate their target genes using super-enhancers include Wnt, TGFb, LIF, BDNF, and NOTCH. [44] [64] [65] [66] [67] The constituent enhancers of super-enhancers physically interact with each other and their target genes over a long range sequence-wise. [12] [46] [68] 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. [4] [5] [11] [49] [56] [59] [69] [70] [71] [72] [73] A similar enrichment in disease-associated sequence variation has also been observed for stretch enhancers. [4]

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. [5] [10] [68] [69] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] Altered super-enhancer function is also induced by mutations of chromatin regulators. [84] Acquired super-enhancers may thus be biomarkers that could be useful for diagnosis and therapeutic intervention. [44]

Proteins enriched at super-enhancers include the targets of small molecules that target transcription-regulating proteins and have been deployed against cancers. [10] [11] [49] [85] 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. [10] [13] [14] [86] 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. [11]

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. [3] [5] [11] [87] [88] [89] 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. [3] 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. [90]

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Richard Allen Young is an American geneticist, a Member of Whitehead Institute, and a professor of biology at the Massachusetts Institute of Technology. He is a pioneer in the systems biology of gene control who has developed genomics technologies and concepts key to understanding gene control in human health and disease. He has served as an advisor to the World Health Organization and the National Institutes of Health. He is a member of the National Academy of Sciences and the National Academy of Medicine. Scientific American has recognized him as one of the top 50 leaders in science, technology and business. Young is among the most Highly Cited Researchers in his field.

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References

  1. ↑ Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA (November 2013). "Super-enhancers in the control of cell identity and disease". Cell. 155 (4): 934–47. doi:10.1016/j.cell.2013.09.053. PMC   3841062 . PMID   24119843.
  2. ↑ Meuleman W, Muratov A, Rynes E, Halow J, Lee K, Bates D, Diegel M, Dunn D, Neri F, Teodosiadis A, Reynolds A, Haugen E, Nelson J, Johnson A, Frerker M, Buckley M, Sandstrom R, Vierstra J, Kaul R, Stamatoyannopoulos J (August 2020). "Index and biological spectrum of human DNase I hypersensitive sites". Nature. 584 (7820): 244–251. Bibcode:2020Natur.584..244M. doi:10.1038/s41586-020-2559-3. PMC   7422677 . PMID   32728217.
  3. 1 2 3 4 5 6 7 8 9 10 Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA (April 2013). "Master transcription factors and mediator establish super-enhancers at key cell identity genes". Cell. 153 (2): 307–19. doi:10.1016/j.cell.2013.03.035. PMC   3653129 . PMID   23582322.
  4. 1 2 3 4 5 6 Parker SC, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, van Bueren KL, Chines PS, Narisu N, Black BL, Visel A, Pennacchio LA, Collins FS (October 2013). "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. Bibcode:2013PNAS..11017921P. doi: 10.1073/pnas.1317023110 . PMC   3816444 . PMID   24127591.
  5. 1 2 3 4 5 6 7 8 9 Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA (November 2013). "Super-enhancers in the control of cell identity and disease". Cell. 155 (4): 934–47. doi:10.1016/j.cell.2013.09.053. PMC   3841062 . PMID   24119843.
  6. 1 2 Tang F, Yang Z, Tan Y, Li Y (2020). "Super-enhancer function and its application in cancer targeted therapy". npj Precis Oncol. 4: 2. doi:10.1038/s41698-020-0108-z. PMC   7016125 . PMID   32128448.
  7. ↑ Saint-André V, Federation AJ, Lin CY, Abraham BJ, Reddy J, Lee TI, Bradner JE, Young RA (March 2016). "Models of human core transcriptional regulatory circuitries". Genome Research. 26 (3): 385–96. doi:10.1101/gr.197590.115. PMC   4772020 . PMID   26843070.
  8. ↑ Wang M, Chen Q, Wang S, Xie H, Liu J, Huang R, Xiang Y, Jiang Y, Tian D, Bian E (July 2023). "Super-enhancers complexes zoom in transcription in cancer". J Exp Clin Cancer Res. 42 (1): 183. doi: 10.1186/s13046-023-02763-5 . PMC   10375641 . PMID   37501079.
  9. ↑ Tang SC, Vijayakumar U, Zhang Y, Fullwood MJ (June 2022). "Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer". Cancers (Basel). 14 (12): 2866. doi: 10.3390/cancers14122866 . PMC   9221043 . PMID   35740532.
  10. 1 2 3 4 5 6 Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, et al. (July 2014). "Targeting transcription regulation in cancer with a covalent CDK7 inhibitor" (PDF). Nature. 511 (7511): 616–20. Bibcode:2014Natur.511..616K. doi:10.1038/nature13393. PMC   4244910 . PMID   25043025.
  11. 1 2 3 4 5 6 7 Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA (April 2013). "Selective inhibition of tumor oncogenes by disruption of super-enhancers". Cell. 153 (2): 320–34. doi:10.1016/j.cell.2013.03.036. PMC   3760967 . PMID   23582323.
  12. 1 2 Dowen JM, Fan ZP, Hnisz D, Ren G, Abraham BJ, Zhang LN, Weintraub AS, Schuijers J, Lee TI, Zhao K, Young RA (October 2014). "Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes". Cell. 159 (2): 374–87. doi:10.1016/j.cell.2014.09.030. PMC   4197132 . PMID   25303531.
  13. 1 2 3 Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, et al. (December 2014). "Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor". Cancer Cell. 26 (6): 909–22. doi:10.1016/j.ccell.2014.10.019. PMC   4261156 . PMID   25490451.
  14. 1 2 3 Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, Abraham BJ, Sharma B, Yeung C, Altabef A, Perez-Atayde A, Wong KK, Yuan GC, Gray NS, Young RA, George RE (November 2014). "CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer". Cell. 159 (5): 1126–39. doi:10.1016/j.cell.2014.10.024. PMC   4243043 . PMID   25416950.
  15. ↑ Cameron A, Wakelin G, Gaulton N, Young LV, Wotherspoon S, Hodson N, Lees MJ, Moore DR, Johnston AP (December 2022). "Identification of underexplored mesenchymal and vascular-related cell populations in human skeletal muscle". Am J Physiol Cell Physiol. 323 (6): C1586–C1600. doi:10.1152/ajpcell.00364.2022. PMID   36342160.
  16. ↑ Ehrlich KC, Paterson HL, Lacey M, Ehrlich M (December 2016). "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. PMC   5168824 . PMID   28018137.
  17. ↑ Michida H, Imoto H, Shinohara H, Yumoto N, Seki M, Umeda M, Hayashi T, Nikaido I, Kasukawa T, Suzuki Y, Okada-Hatakeyama M (June 2020). "The Number of Transcription Factors at an Enhancer Determines Switch-like Gene Expression". Cell Rep. 31 (9): 107724. doi:10.1016/j.celrep.2020.107724. PMID   32492432.
  18. ↑ Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA (April 2013). "Master transcription factors and mediator establish super-enhancers at key cell identity genes". Cell. 153 (2): 307–19. doi:10.1016/j.cell.2013.03.035. PMC   3653129 . PMID   23582322.
  19. ↑ Quevedo M, Meert L, Dekker MR, Dekkers DH, Brandsma JH, van den Berg DL, Ozgür Z, van IJcken WF, Demmers J, Fornerod M, Poot RA (June 2019). "Mediator complex interaction partners organize the transcriptional network that defines neural stem cells". Nat Commun. 10 (1): 2669. Bibcode:2019NatCo..10.2669Q. doi:10.1038/s41467-019-10502-8. PMC   6573065 . PMID   31209209.
  20. ↑ Mills C, Muruganujan A, Ebert D, Marconett CN, Lewinger JP, Thomas PD, Mi H (2020). "PEREGRINE: A genome-wide prediction of enhancer to gene relationships supported by experimental evidence". PLOS ONE. 15 (12): e0243791. Bibcode:2020PLoSO..1543791M. doi: 10.1371/journal.pone.0243791 . PMC   7737992 . PMID   33320871.
  21. ↑ Duffy MJ, O'Grady S, Tang M, Crown J (March 2021). "MYC as a target for cancer treatment". Cancer Treat Rev. 94: 102154. doi:10.1016/j.ctrv.2021.102154. PMID   33524794.
  22. ↑ Schaub FX, Dhankani V, Berger AC, Trivedi M, Richardson AB, Shaw R, Zhao W, Zhang X, Ventura A, Liu Y, Ayer DE, Hurlin PJ, Cherniack AD, Eisenman RN, Bernard B, Grandori C (March 2018). "Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas". Cell Syst. 6 (3): 282–300.e2. doi:10.1016/j.cels.2018.03.003. PMC   5892207 . PMID   29596783.
  23. ↑ Schuijers J, Manteiga JC, Weintraub AS, Day DS, Zamudio AV, Hnisz D, Lee TI, Young RA (April 2018). "Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism". Cell Rep. 23 (2): 349–360. doi:10.1016/j.celrep.2018.03.056. PMC   5929158 . PMID   29641996.
  24. ↑ Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA (November 2013). "Super-enhancers in the control of cell identity and disease". Cell. 155 (4): 934–47. doi:10.1016/j.cell.2013.09.053. PMC   3841062 . PMID   24119843.
  25. 1 2 Singh G, Mullany S, Moorthy SD, Zhang R, Mehdi T, Tian R, Duncan AG, Moses AM, Mitchell JA (April 2021). "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. doi:10.1101/gr.272468.120. PMC   8015845 . PMID   33712417.
  26. ↑ Boyle AP, Davis S, Shulha HP, Meltzer P, Margulies EH, Weng Z, Furey TS, Crawford GE (January 2008). "High-resolution mapping and characterization of open chromatin across the genome". Cell. 132 (2): 311–22. doi:10.1016/j.cell.2007.12.014. PMC   2669738 . PMID   18243105.
  27. ↑ Williams K, Carrasquilla GD, Ingerslev LR, Hochreuter MY, Hansson S, Pillon NJ, Donkin I, Versteyhe S, Zierath JR, Kilpeläinen TO, Barrès R (November 2021). "Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in whole-body function and human health". Mol Metab. 53: 101290. doi:10.1016/j.molmet.2021.101290. PMC   8355925 . PMID   34252634.
  28. ↑ Stormberg T, Filliaux S, Baughman HE, Komives EA, Lyubchenko YL (September 2021). "Transcription factor NF-κB unravels nucleosomes". Biochim Biophys Acta Gen Subj. 1865 (9): 129934. doi:10.1016/j.bbagen.2021.129934. PMC   8277743 . PMID   34029641.
  29. ↑ Huang B, Yang XD, Zhou MM, Ozato K, Chen LF (March 2009). "Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA". Mol Cell Biol. 29 (5): 1375–87. doi:10.1128/MCB.01365-08. PMC   2643823 . PMID   19103749.
  30. ↑ Devaiah BN, Case-Borden C, Gegonne A, Hsu CH, Chen Q, Meerzaman D, Dey A, Ozato K, Singer DS (June 2016). "BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin". Nat Struct Mol Biol. 23 (6): 540–8. doi:10.1038/nsmb.3228. PMC   4899182 . PMID   27159561.
  31. ↑ Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K (August 2005). "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. doi:10.1016/j.molcel.2005.06.027. PMID   16109376.
  32. ↑ Richter WF, Nayak S, Iwasa J, Taatjes DJ (November 2022). "The Mediator complex as a master regulator of transcription by RNA polymerase II". Nat Rev Mol Cell Biol. 23 (11): 732–749. doi:10.1038/s41580-022-00498-3. PMC   9207880 . PMID   35725906.
  33. ↑ Ramasamy S, Aljahani A, Karpinska MA, Cao TB, Velychko T, Cruz JN, Lidschreiber M, Oudelaar AM (July 2023). "The Mediator complex regulates enhancer-promoter interactions". Nat Struct Mol Biol. 30 (7): 991–1000. doi:10.1038/s41594-023-01027-2. PMC   10352134 . PMID   37430065.
  34. ↑ Banerji J, Rusconi S, Schaffner W (December 1981). "Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences". Cell. 27 (2 Pt 1): 299–308. doi:10.1016/0092-8674(81)90413-x. PMID   6277502. S2CID   54234674.
  35. ↑ Benoist C, Chambon P (March 1981). "In vivo sequence requirements of the SV40 early promoter region". Nature. 290 (5804): 304–10. Bibcode:1981Natur.290..304B. doi:10.1038/290304a0. PMID   6259538. S2CID   4263279.
  36. ↑ Gruss P, Dhar R, Khoury G (February 1981). "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. Bibcode:1981PNAS...78..943G. doi: 10.1073/pnas.78.2.943 . PMC   319921 . PMID   6262784.
  37. ↑ Evans T, Felsenfeld G, Reitman M (1990). "Control of globin gene transcription". Annual Review of Cell Biology. 6: 95–124. doi:10.1146/annurev.cb.06.110190.000523. PMID   2275826.
  38. ↑ Cellier M, Belouchi A, Gros P (June 1996). "Resistance to intracellular infections: comparative genomic analysis of Nramp". Trends in Genetics. 12 (6): 201–4. doi:10.1016/0168-9525(96)30042-5. PMID   8928221.
  39. ↑ Li Q, Peterson KR, Fang X, Stamatoyannopoulos G (November 2002). "Locus control regions". Blood. 100 (9): 3077–86. doi:10.1182/blood-2002-04-1104. PMC   2811695 . PMID   12384402.
  40. ↑ Grosveld F, van Assendelft GB, Greaves DR, Kollias G (December 1987). "Position-independent, high-level expression of the human beta-globin gene in transgenic mice". Cell. 51 (6): 975–85. doi:10.1016/0092-8674(87)90584-8. hdl: 1765/2425 . PMID   3690667. S2CID   1150699.
  41. ↑ Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, et al. (March 2010). "A map of open chromatin in human pancreatic islets". Nature Genetics. 42 (3): 255–9. doi:10.1038/ng.530. PMC   2828505 . PMID   20118932.
  42. ↑ Koch F, Fenouil R, Gut M, Cauchy P, Albert TK, Zacarias-Cabeza J, Spicuglia S, de la Chapelle AL, Heidemann M, Hintermair C, Eick D, Gut I, Ferrier P, Andrau JC (August 2011). "Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters". Nature Structural & Molecular Biology. 18 (8): 956–63. doi:10.1038/nsmb.2085. PMID   21765417. S2CID   12778976.
  43. 1 2 3 Pott S, Lieb JD (January 2015). "What are super-enhancers?". Nature Genetics. 47 (1): 8–12. doi:10.1038/ng.3167. PMID   25547603. S2CID   205349376.
  44. 1 2 3 4 5 6 7 8 Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, Bradner JE, Young RA (April 2015). "Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers". Molecular Cell. 58 (2): 362–70. doi:10.1016/j.molcel.2015.02.014. PMC   4402134 . PMID   25801169.
  45. ↑ Di Micco R, Fontanals-Cirera B, Low V, Ntziachristos P, Yuen SK, Lovell CD, et al. (October 2014). "Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes". Cell Reports. 9 (1): 234–47. doi:10.1016/j.celrep.2014.08.055. PMC   4317728 . PMID   25263550.
  46. 1 2 Ji X, Dadon DB, Powell BE, Fan ZP, Borges-Rivera D, Shachar S, Weintraub AS, Hnisz D, Pegoraro G, Lee TI, Misteli T, Jaenisch R, Young RA (February 2016). "3D Chromosome Regulatory Landscape of Human Pluripotent Cells". Cell Stem Cell. 18 (2): 262–75. doi:10.1016/j.stem.2015.11.007. PMC   4848748 . PMID   26686465.
  47. ↑ Tsankov AM, Gu H, Akopian V, Ziller MJ, Donaghey J, Amit I, Gnirke A, Meissner A (February 2015). "Transcription factor binding dynamics during human ES cell differentiation". Nature. 518 (7539): 344–9. Bibcode:2015Natur.518..344T. doi:10.1038/nature14233. PMC   4499331 . PMID   25693565.
  48. ↑ Fang Z, Hecklau K, Gross F, Bachmann I, Venzke M, Karl M, Schuchhardt J, Radbruch A, Herzel H, Baumgrass R (November 2015). "Transcription factor co-occupied regions in the murine genome constitute T-helper-cell subtype-specific enhancers". European Journal of Immunology. 45 (11): 3150–7. doi: 10.1002/eji.201545713 . PMID   26300430.
  49. 1 2 3 Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ (April 2015). "Super-enhancers delineate disease-associated regulatory nodes in T cells". Nature. 520 (7548): 558–62. Bibcode:2015Natur.520..558V. doi:10.1038/nature14154. PMC   4409450 . PMID   25686607.
  50. ↑ Koues OI, Kowalewski RA, Chang LW, Pyfrom SC, Schmidt JA, Luo H, Sandoval LE, Hughes TB, Bednarski JJ, Cashen AF, Payton JE, Oltz EM (January 2015). "Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma". Immunity. 42 (1): 186–98. doi:10.1016/j.immuni.2014.12.021. PMC   4302272 . PMID   25607463.
  51. ↑ Adam RC, Yang H, Rockowitz S, Larsen SB, Nikolova M, Oristian DS, Polak L, Kadaja M, Asare A, Zheng D, Fuchs E (May 2015). "Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice". Nature. 521 (7552): 366–70. Bibcode:2015Natur.521..366A. doi:10.1038/nature14289. PMC   4482136 . PMID   25799994.
  52. ↑ Siersbæk R, Baek S, Rabiee A, Nielsen R, Traynor S, Clark N, Sandelin A, Jensen ON, Sung MH, Hager GL, Mandrup S (June 2014). "Molecular architecture of transcription factor hotspots in early adipogenesis". Cell Reports. 7 (5): 1434–42. doi:10.1016/j.celrep.2014.04.043. PMC   6360525 . PMID   24857666.
  53. ↑ Siersbæk R, Rabiee A, Nielsen R, Sidoli S, Traynor S, Loft A, La Cour Poulsen L, Rogowska-Wrzesinska A, Jensen ON, Mandrup S (June 2014). "Transcription factor cooperativity in early adipogenic hotspots and super-enhancers". Cell Reports. 7 (5): 1443–55. doi: 10.1016/j.celrep.2014.04.042 . PMID   24857652.
  54. ↑ Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T, et al. (April 2014). "Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice". Cell Metabolism. 19 (4): 593–604. doi:10.1016/j.cmet.2014.03.007. PMC   4012340 . PMID   24703692.
  55. ↑ Loft A, Forss I, Siersbæk MS, Schmidt SF, Larsen AS, Madsen JG, Pisani DF, Nielsen R, Aagaard MM, Mathison A, Neville MJ, Urrutia R, Karpe F, Amri EZ, Mandrup S (January 2015). "Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers". Genes & Development. 29 (1): 7–22. doi:10.1101/gad.250829.114. PMC   4281566 . PMID   25504365.
  56. 1 2 Pasquali L, Gaulton KJ, Rodríguez-Seguí SA, Mularoni L, Miguel-Escalada I, Akerman I, et al. (February 2014). "Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants". Nature Genetics. 46 (2): 136–43. doi:10.1038/ng.2870. PMC   3935450 . PMID   24413736.
  57. ↑ Liu CF, Lefebvre V (September 2015). "The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis". Nucleic Acids Research. 43 (17): 8183–203. doi:10.1093/nar/gkv688. PMC   4787819 . PMID   26150426.
  58. ↑ Ohba S, He X, Hojo H, McMahon AP (July 2015). "Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte". Cell Reports. 12 (2): 229–43. doi:10.1016/j.celrep.2015.06.013. PMC   4504750 . PMID   26146088.
  59. 1 2 Kaikkonen MU, Niskanen H, Romanoski CE, Kansanen E, Kivelä AM, Laitalainen J, Heinz S, Benner C, Glass CK, Ylä-Herttuala S (November 2014). "Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization". Nucleic Acids Research. 42 (20): 12570–84. doi:10.1093/nar/gku1036. PMC   4227755 . PMID   25352550.
  60. ↑ Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, Glass CK (December 2014). "Environment drives selection and function of enhancers controlling tissue-specific macrophage identities". Cell. 159 (6): 1327–40. doi:10.1016/j.cell.2014.11.023. PMC   4364385 . PMID   25480297.
  61. ↑ Sun J, Rockowitz S, Xie Q, Ashery-Padan R, Zheng D, Cvekl A (August 2015). "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. doi:10.1093/nar/gkv589. PMC   4538810 . PMID   26138486.
  62. ↑ Beagrie RA, Scialdone A, Schueler M, Kraemer DC, Chotalia M, Xie SQ, Barbieri M, de Santiago I, Lavitas LM, Branco MR, Fraser J, Dostie J, Game L, Dillon N, Edwards PA, Nicodemi M, Pombo A (March 2017). "Complex multi-enhancer contacts captured by Genome Architecture Mapping (GAM)". Nature. 543 (7646): 519–524. Bibcode:2017Natur.543..519B. doi:10.1038/nature21411. PMC   5366070 . PMID   28273065.
  63. ↑ Quinodoz SA, Ollikainen N, Tabak B, Palla A, Schmidt JM, Detmar E, Lai MM, Shishkin AA, Bhat P, Takei Y, Trinh V, Aznauryan E, Russell P, Cheng C, Jovanovic M, Chow A, Cai L, McDonel P, Garber M, Guttman M (June 2018). "Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus". Cell. 174 (3): 744–757. doi:10.1016/j.cell.2018.05.024. PMC   6548320 . PMID   29887377.
  64. ↑ Joo JY, Schaukowitch K, Farbiak L, Kilaru G, Kim TK (January 2016). "Stimulus-specific combinatorial functionality of neuronal c-fos enhancers". Nature Neuroscience. 19 (1): 75–83. doi:10.1038/nn.4170. PMC   4696896 . PMID   26595656.
  65. ↑ Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L, Wendorff AA, Xu L, Castillo-Martin M, Llobet-Navás D, Cordon-Cardo C, Clappier E, Soulier J, Ferrando AA (October 2014). "A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia". Nature Medicine. 20 (10): 1130–7. doi:10.1038/nm.3665. PMC   4192073 . PMID   25194570.
  66. ↑ Wang H, Zang C, Taing L, Arnett KL, Wong YJ, Pear WS, Blacklow SC, Liu XS, Aster JC (January 2014). "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. Bibcode:2014PNAS..111..705W. doi: 10.1073/pnas.1315023111 . PMC   3896193 . PMID   24374627.
  67. ↑ Yashiro-Ohtani Y, Wang H, Zang C, Arnett KL, Bailis W, Ho Y, et al. (November 2014). "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. Bibcode:2014PNAS..111E4946Y. doi: 10.1073/pnas.1407079111 . PMC   4246292 . PMID   25369933.
  68. 1 2 Hnisz D, Weintraub AS, Day DS, Valton AL, Bak RO, Li CH, Goldmann J, Lajoie BR, Fan ZP, Sigova AA, Reddy J, Borges-Rivera D, Lee TI, Jaenisch R, Porteus MH, Dekker J, Young RA (March 2016). "Activation of proto-oncogenes by disruption of chromosome neighborhoods". Science. 351 (6280): 1454–8. Bibcode:2016Sci...351.1454H. doi:10.1126/science.aad9024. PMC   4884612 . PMID   26940867.
  69. 1 2 Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD, Etchin J, Lawton L, Sallan SE, Silverman LB, Loh ML, Hunger SP, Sanda T, Young RA, Look AT (December 2014). "Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element". Science. 346 (6215): 1373–7. doi:10.1126/science.1259037. PMC   4720521 . PMID   25394790.
  70. ↑ Cavalli G, Hayashi M, Jin Y, Yorgov D, Santorico SA, Holcomb C, Rastrou M, Erlich H, Tengesdal IW, Dagna L, Neff CP, Palmer BE, Spritz RA, Dinarello CA (February 2016). "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. Bibcode:2016PNAS..113.1363C. doi: 10.1073/pnas.1523482113 . PMC   4747741 . PMID   26787888.
  71. ↑ Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, Beik S, Shoresh N, Whitton H, Ryan RJ, Shishkin AA, Hatan M, Carrasco-Alfonso MJ, Mayer D, Luckey CJ, Patsopoulos NA, De Jager PL, Kuchroo VK, Epstein CB, Daly MJ, Hafler DA, Bernstein BE (February 2015). "Genetic and epigenetic fine mapping of causal autoimmune disease variants". Nature. 518 (7539): 337–43. Bibcode:2015Natur.518..337F. doi:10.1038/nature13835. PMC   4336207 . PMID   25363779.
  72. ↑ Weinstein JS, Lezon-Geyda K, Maksimova Y, Craft S, Zhang Y, Su M, Schulz VP, Craft J, Gallagher PG (December 2014). "Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes". Blood. 124 (25): 3719–29. doi:10.1182/blood-2014-06-582700. PMC   4263981 . PMID   25331115.
  73. ↑ Oldridge DA, Wood AC, Weichert-Leahey N, Crimmins I, Sussman R, Winter C, et al. (December 2015). "Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism". Nature. 528 (7582): 418–21. Bibcode:2015Natur.528..418O. doi:10.1038/nature15540. PMC   4775078 . PMID   26560027.
  74. ↑ Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, Garbitt VM, Riggs DL, Brents LA, Roschke AV, Van Wier S, Fonseca R, Bergsagel PL, Kuehl WM (August 2014). "Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma". Leukemia. 28 (8): 1725–35. doi:10.1038/leu.2014.70. PMC   4126852 . PMID   24518206.
  75. ↑ Drier Y, Cotton MJ, Williamson KE, Gillespie SM, Ryan RJ, Kluk MJ, et al. (March 2016). "An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma". Nature Genetics. 48 (3): 265–72. doi:10.1038/ng.3502. PMC   4767593 . PMID   26829750.
  76. ↑ Northcott PA, Lee C, Zichner T, Stütz AM, Erkek S, Kawauchi D, et al. (July 2014). "Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma". Nature. 511 (7510): 428–34. Bibcode:2014Natur.511..428N. doi:10.1038/nature13379. PMC   4201514 . PMID   25043047.
  77. ↑ Walker BA, Wardell CP, Brioli A, Boyle E, Kaiser MF, Begum DB, Dahir NB, Johnson DC, Ross FM, Davies FE, Morgan GJ (14 March 2014). "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. doi:10.1038/bcj.2014.13. PMC   3972699 . PMID   24632883.
  78. ↑ Gröschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BA, Erpelinck C, et al. (April 2014). "A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia". Cell. 157 (2): 369–81. doi: 10.1016/j.cell.2014.02.019 . PMID   24703711.
  79. ↑ Shi J, Whyte WA, Zepeda-Mendoza CJ, Milazzo JP, Shen C, Roe JS, et al. (December 2013). "Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation". Genes & Development. 27 (24): 2648–62. doi:10.1101/gad.232710.113. PMC   3877755 . PMID   24285714.
  80. ↑ Kennedy AL, Vallurupalli M, Chen L, Crompton B, Cowley G, Vazquez F, Weir BA, Tsherniak A, Parasuraman S, Kim S, Alexe G, Stegmaier K (October 2015). "Functional, chemical genomic, and super-enhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma". Oncotarget. 6 (30): 30178–93. doi:10.18632/oncotarget.4903. PMC   4745789 . PMID   26337082.
  81. ↑ Tomazou EM, Sheffield NC, Schmidl C, Schuster M, Schönegger A, Datlinger P, Kubicek S, Bock C, Kovar H (February 2015). "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. doi:10.1016/j.celrep.2015.01.042. PMC   4542316 . PMID   25704812.
  82. ↑ Nabet B, Ó Broin P, Reyes JM, Shieh K, Lin CY, Will CM, Popovic R, Ezponda T, Bradner JE, Golden AA, Licht JD (August 2015). "Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape". Cell Reports. 12 (8): 1300–13. doi: 10.1016/j.celrep.2015.06.078 . PMC   4551578 . PMID   26279576.
  83. ↑ Zhang X, Choi PS, Francis JM, Imielinski M, Watanabe H, Cherniack AD, Meyerson M (February 2016). "Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers". Nature Genetics. 48 (2): 176–82. doi:10.1038/ng.3470. PMC   4857881 . PMID   26656844.
  84. ↑ Hodges HC, Stanton BZ, Cermakova K, Chang CY, Miller EL, Kirkland JG, Ku WL, Veverka V, Zhao K, Crabtree GR (January 2018). "Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers". Nature Structural & Molecular Biology. 25 (1): 61–72. doi:10.1038/s41594-017-0007-3. PMC   5909405 . PMID   29323272.
  85. ↑ Porcher C (April 2015). "Toward a BETter grasp of acetyl-lysine readers". Blood. 125 (18): 2739–41. doi: 10.1182/blood-2015-03-630830 . PMID   25931578.
  86. ↑ Wang Y, Zhang T, Kwiatkowski N, Abraham BJ, Lee TI, Xie S, Yuzugullu H, Von T, Li H, Lin Z, Stover DG, Lim E, Wang ZC, Iglehart JD, Young RA, Gray NS, Zhao JJ (September 2015). "CDK7-dependent transcriptional addiction in triple-negative breast cancer". Cell. 163 (1): 174–86. doi: 10.1016/j.cell.2015.08.063 . PMC   4583659 . PMID   26406377.
  87. ↑ Wei Y, Zhang S, Shang S, Zhang B, Li S, Wang X, Wang F, Su J, Wu Q, Liu H, Zhang Y (January 2016). "SEA: a super-enhancer archive". Nucleic Acids Research. 44 (D1): D172-9. doi:10.1093/nar/gkv1243. PMC   4702879 . PMID   26578594.
  88. ↑ Khan A, Zhang X (January 2016). "dbSUPER: a database of super-enhancers in mouse and human genome". Nucleic Acids Research. 44 (D1): D164-71. doi:10.1093/nar/gkv1002. PMC   4702767 . PMID   26438538.
  89. ↑ Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, Hanna J, Lodato MA, Frampton GM, Sharp PA, Boyer LA, Young RA, Jaenisch R (December 2010). "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. doi: 10.1073/pnas.1016071107 . PMC   3003124 . PMID   21106759.
  90. ↑ Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK (May 2010). "Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities". Molecular Cell. 38 (4): 576–89. doi:10.1016/j.molcel.2010.05.004. PMC   2898526 . PMID   20513432.
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