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超级强化子

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维基百科，自由的百科全书

在遗传学，超级强化子（Super-enhancer）是哺乳类基因体中包含多个强化子的区域，可以结合许多转录因子来启动决定细胞分化结果之基因的转录。[1][2][3]由于超级强化子经常出现于控制、定义细胞身份基因的附近，因此它们也可被用来快速定位基因组中调控细胞身份的关键位点。[3][4]

超级强化子会与许多与转录调控相关的蛋白结合，并常用于调控高表现量的基因表现[1][5][6][7]与超级强化子相关的基因表现会特别对扰动敏感，可能控制细胞状态的转换，这也导致由超级强化子调控的基因常对影响转录的小分子较为敏感。[1][5][6][8][9]

历史[编辑]

有关强化子对转录调控的研究始于1980年代。[10][11][12][13][14] 不久后发现了一些大型或多单元的转录调控区域，包含基因座控制区、成簇的开放调控元件与转录起始的平台等。[15][16][17][18]近期的研究结果表明，这些不同类别的调控单元可能都属于超级强化子。[19]

2013年，两组研究团队分别在基因组中对决定细胞分化种类重要的位点附近发现了大型强化子，其中理查德·杨（英语：Richard A. Young）的团队发现了超级强化子，法兰西斯·柯林斯的团队则发现了延伸强化子（stretch enhancers）。[20][21]超级强化子及延伸强化子皆为成簇的强化子，控制了细胞中特定的基因表现，可能是极为相似的元件。[21][22]

根据目前定义，“超级强化子”一词由美国遗传学家理查德·杨的团队定义，用来描述在小鼠的胚胎干细胞中发现[20]、长度较长、且能控制影响干细胞分化结果之基因（包括Oct-4、Sox2、Nanog、KLF4 以及 Esrrb等）表现的特定元件。干扰调控这些基因的超级强化子会严重影响这些基因的表现。[22]超级强化子已经在一些小鼠与人类组织的基因组中，负责控制细胞分化结果之基因附近被发现。[21][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]

功能[编辑]

相关疾病[编辑]

侦测方式[编辑]

超级强化子的侦测方式，大多是以染色质免疫沉淀-测序侦测主要转录因子、中介体（英语：Mediator (coactivator)）与BRD4蛋白（英语：BRD4）等共同因子（英语：Transcription coregulator）或H3K27ac核小体（英语：H3K27ac）在基因组中的结合位点，其中以H3K27ac核小体最为常用。[1][3][6][41][42][43]理察·杨的团队开发了一个称为“ROSE”（Rank Ordering of Super-Enhancers）的程式，可用于从染色质免疫沉淀定序的结果中侦测超级强化子，这个程式可依据超级强化子中某些标记的含量比一般强化子更多的特性，判定数个已知的强化子是否组成超级强化子，而用以判定的间距标准可依不同情况调整。[1]

参考资料[编辑]

  1. ^ 1.0 1.1 1.2 1.3 1.4 Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. April 2013, 153 (2): 307–19. PMC 3653129 可免费查阅. PMID 23582322. doi:10.1016/j.cell.2013.03.035. 
  2. ^ 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. 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. October 2013, 110 (44): 17921–6. PMC 3816444 可免费查阅. PMID 24127591. doi:10.1073/pnas.1317023110. 
  3. ^ 3.0 3.1 3.2 Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA. Super-enhancers in the control of cell identity and disease. Cell. November 2013, 155 (4): 934–47. PMC 3841062 可免费查阅. PMID 24119843. doi:10.1016/j.cell.2013.09.053. 
  4. ^ Saint-André V, Federation AJ, Lin CY, Abraham BJ, Reddy J, Lee TI, Bradner JE, Young RA. Models of human core transcriptional regulatory circuitries. Genome Research. March 2016, 26 (3): 385–96. PMC 4772020 可免费查阅. PMID 26843070. doi:10.1101/gr.197590.115. 
  5. ^ 5.0 5.1 Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor (PDF). Nature. July 2014, 511 (7511): 616–20 [2019-02-16]. PMC 4244910 可免费查阅. PMID 25043025. doi:10.1038/nature13393. （原始内容 (PDF)存档于2018-11-04）. 
  6. ^ 6.0 6.1 6.2 Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. April 2013, 153 (2): 320–34. PMC 3760967 可免费查阅. PMID 23582323. doi:10.1016/j.cell.2013.03.036. 
  7. ^ Dowen JM, Fan ZP, Hnisz D, Ren G, Abraham BJ, Zhang LN, Weintraub AS, Schuijers J, Lee TI, Zhao K, Young RA. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell. October 2014, 159 (2): 374–87. PMC 4197132 可免费查阅. PMID 25303531. doi:10.1016/j.cell.2014.09.030. 
  8. ^ Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. December 2014, 26 (6): 909–22. PMC 4261156 可免费查阅. PMID 25490451. doi:10.1016/j.ccell.2014.10.019. 
  9. ^ 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. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. November 2014, 159 (5): 1126–39. PMC 4243043 可免费查阅. PMID 25416950. doi:10.1016/j.cell.2014.10.024. 
  10. ^ Banerji J, Rusconi S, Schaffner W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell. December 1981, 27 (2 Pt 1): 299–308. PMID 6277502. doi:10.1016/0092-8674(81)90413-x. 
  11. ^ Benoist C, Chambon P. In vivo sequence requirements of the SV40 early promotor region. Nature. March 1981, 290 (5804): 304–10. PMID 6259538. doi:10.1038/290304a0. 
  12. ^ Gruss P, Dhar R, Khoury G. 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. February 1981, 78 (2): 943–7. PMC 319921 可免费查阅. PMID 6262784. doi:10.1073/pnas.78.2.943. 
  13. ^ Evans T, Felsenfeld G, Reitman M. Control of globin gene transcription. Annual Review of Cell Biology. 1990, 6: 95–124. PMID 2275826. doi:10.1146/annurev.cb.06.110190.000523. 
  14. ^ Cellier M, Belouchi A, Gros P. Resistance to intracellular infections: comparative genomic analysis of Nramp. Trends in Genetics. June 1996, 12 (6): 201–4. PMID 8928221. doi:10.1016/0168-9525(96)30042-5. 
  15. ^ Li Q, Peterson KR, Fang X, Stamatoyannopoulos G. Locus control regions. Blood. November 2002, 100 (9): 3077–86. PMC 2811695 可免费查阅. PMID 12384402. doi:10.1182/blood-2002-04-1104. 
  16. ^ Grosveld F, van Assendelft GB, Greaves DR, Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. December 1987, 51 (6): 975–85. PMID 3690667. doi:10.1016/0092-8674(87)90584-8. 
  17. ^ Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, et al. A map of open chromatin in human pancreatic islets. Nature Genetics. March 2010, 42 (3): 255–9. PMC 2828505 可免费查阅. PMID 20118932. doi:10.1038/ng.530. 
  18. ^ 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. Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Nature Structural & Molecular Biology. August 2011, 18 (8): 956–63. PMID 21765417. doi:10.1038/nsmb.2085. 
  19. ^ Pott S, Lieb JD. What are super-enhancers?. Nature Genetics. January 2015, 47 (1): 8–12. PMID 25547603. doi:10.1038/ng.3167. 
  20. ^ 20.0 20.1 Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. April 2013, 153 (2): 307–19. PMC 3653129 可免费查阅. PMID 23582322. doi:10.1016/j.cell.2013.03.035. 
  21. ^ 21.0 21.1 21.2 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. 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. October 2013, 110 (44): 17921–6. PMC 3816444 可免费查阅. PMID 24127591. doi:10.1073/pnas.1317023110. 
  22. ^ 22.0 22.1 Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, Bradner JE, Young RA. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Molecular Cell. April 2015, 58 (2): 362–70. PMC 4402134 可免费查阅. PMID 25801169. doi:10.1016/j.molcel.2015.02.014. 
  23. ^ Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA. Super-enhancers in the control of cell identity and disease. Cell. November 2013, 155 (4): 934–47. PMC 3841062 可免费查阅. PMID 24119843. doi:10.1016/j.cell.2013.09.053. 
  24. ^ Di Micco R, Fontanals-Cirera B, Low V, Ntziachristos P, Yuen SK, Lovell CD, et al. Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Reports. October 2014, 9 (1): 234–47. PMC 4317728 可免费查阅. PMID 25263550. doi:10.1016/j.celrep.2014.08.055. 
  25. ^ 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. 3D Chromosome Regulatory Landscape of Human Pluripotent Cells. Cell Stem Cell. February 2016, 18 (2): 262–75. PMID 26686465. doi:10.1016/j.stem.2015.11.007. 
  26. ^ Tsankov AM, Gu H, Akopian V, Ziller MJ, Donaghey J, Amit I, Gnirke A, Meissner A. Transcription factor binding dynamics during human ES cell differentiation. Nature. February 2015, 518 (7539): 344–9. PMC 4499331 可免费查阅. PMID 25693565. doi:10.1038/nature14233. 
  27. ^ Fang Z, Hecklau K, Gross F, Bachmann I, Venzke M, Karl M, Schuchhardt J, Radbruch A, Herzel H, Baumgrass R. Transcription factor co-occupied regions in the murine genome constitute T-helper-cell subtype-specific enhancers. European Journal of Immunology. November 2015, 45 (11): 3150–7. PMID 26300430. doi:10.1002/eji.201545713. 
  28. ^ 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. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature. April 2015, 520 (7548): 558–62. PMC 4409450 可免费查阅. PMID 25686607. doi:10.1038/nature14154. 
  29. ^ Koues OI, Kowalewski RA, Chang LW, Pyfrom SC, Schmidt JA, Luo H, Sandoval LE, Hughes TB, Bednarski JJ, Cashen AF, Payton JE, Oltz EM. Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma. Immunity. January 2015, 42 (1): 186–98. PMC 4302272 可免费查阅. PMID 25607463. doi:10.1016/j.immuni.2014.12.021. 
  30. ^ Adam RC, Yang H, Rockowitz S, Larsen SB, Nikolova M, Oristian DS, Polak L, Kadaja M, Asare A, Zheng D, Fuchs E. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature. May 2015, 521 (7552): 366–70. PMC 4482136 可免费查阅. PMID 25799994. doi:10.1038/nature14289. 
  31. ^ Siersbæk R, Baek S, Rabiee A, Nielsen R, Traynor S, Clark N, Sandelin A, Jensen ON, Sung MH, Hager GL, Mandrup S. Molecular architecture of transcription factor hotspots in early adipogenesis. Cell Reports. June 2014, 7 (5): 1434–42. PMID 24857666. doi:10.1016/j.celrep.2014.04.043. 
  32. ^ Siersbæk R, Rabiee A, Nielsen R, Sidoli S, Traynor S, Loft A, La Cour Poulsen L, Rogowska-Wrzesinska A, Jensen ON, Mandrup S. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Reports. June 2014, 7 (5): 1443–55. PMID 24857652. doi:10.1016/j.celrep.2014.04.042. 
  33. ^ Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T, et al. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metabolism. April 2014, 19 (4): 593–604. PMC 4012340 可免费查阅. PMID 24703692. doi:10.1016/j.cmet.2014.03.007. 
  34. ^ 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. Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers. Genes & Development. January 2015, 29 (1): 7–22. PMC 4281566 可免费查阅. PMID 25504365. doi:10.1101/gad.250829.114. 
  35. ^ Pasquali L, Gaulton KJ, Rodríguez-Seguí SA, Mularoni L, Miguel-Escalada I, Akerman I, et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nature Genetics. February 2014, 46 (2): 136–43. PMC 3935450 可免费查阅. PMID 24413736. doi:10.1038/ng.2870. 
  36. ^ Liu CF, Lefebvre V. The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis. Nucleic Acids Research. September 2015, 43 (17): 8183–203. PMC 4787819 可免费查阅. PMID 26150426. doi:10.1093/nar/gkv688. 
  37. ^ Ohba S, He X, Hojo H, McMahon AP. Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte. Cell Reports. July 2015, 12 (2): 229–43. PMC 4504750 可免费查阅. PMID 26146088. doi:10.1016/j.celrep.2015.06.013. 
  38. ^ Kaikkonen MU, Niskanen H, Romanoski CE, Kansanen E, Kivelä AM, Laitalainen J, Heinz S, Benner C, Glass CK, Ylä-Herttuala S. Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization. Nucleic Acids Research. November 2014, 42 (20): 12570–84. PMC 4227755 可免费查阅. PMID 25352550. doi:10.1093/nar/gku1036. 
  39. ^ Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, Glass CK. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. December 2014, 159 (6): 1327–40. PMC 4364385 可免费查阅. PMID 25480297. doi:10.1016/j.cell.2014.11.023. 
  40. ^ Sun J, Rockowitz S, Xie Q, Ashery-Padan R, Zheng D, Cvekl A. 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. August 2015, 43 (14): 6827–46. PMC 4538810 可免费查阅. PMID 26138486. doi:10.1093/nar/gkv589. 
  41. ^ Wei Y, Zhang S, Shang S, Zhang B, Li S, Wang X, Wang F, Su J, Wu Q, Liu H, Zhang Y. SEA: a super-enhancer archive. Nucleic Acids Research. January 2016, 44 (D1): D172–9. PMC 4702879 可免费查阅. PMID 26578594. doi:10.1093/nar/gkv1243. 
  42. ^ Khan A, Zhang X. dbSUPER: a database of super-enhancers in mouse and human genome. Nucleic Acids Research. January 2016, 44 (D1): D164–71. PMC 4702767 可免费查阅. PMID 26438538. doi:10.1093/nar/gkv1002. 
  43. ^ 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. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proceedings of the National Academy of Sciences of the United States of America. December 2010, 107 (50): 21931–6. PMC 3003124 可免费查阅. PMID 21106759. doi:10.1073/pnas.1016071107. 
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