表观遗传调控pre-mRNA的选择性剪接
收稿日期: 2013-09-30
修回日期: 2013-11-12
网络出版日期: 2014-02-25
基金资助
国家自然科学基金面上项目(编号：30972535), 江苏省自然科学基金面上项目(编号：BK2012724)和南京大学大学生创新创业训练计划项目(编号：G1310284100)资助
The epigenetic effect on pre-mRNA alternative splicing
Received date: 2013-09-30
Revised date: 2013-11-12
Online published: 2014-02-25
选择性剪接是真核生物基因表达过程中的关键环节, 是蛋白质多样性的主要来源, 在生物的分化、发育及疾病的发生中扮演重要角色。传统的选择性剪接调控机制的研究多集中于RNA序列元件及与之相关的一些剪接因子, 但近期的突破性研究指出表观遗传因素在选择性剪接的调控中发挥重要作用。DNA甲基化、染色质结构、组蛋白修饰相互影响并作用于pre-mRNA的选择性剪接, 构成一个庞大、复杂的调控网络, 表明表观遗传因素不仅决定着基因转录的起始, 还影响其转录本剪接的结果。文章综述了近年来pre-mRNA选择性剪接的表观遗传调控的研究进展, 探讨了DNA甲基化、染色质结构、组蛋白修饰在pre-mRNA选择性剪接中的可能作用, 并展望了其对人类疾病研究所带来的深远影响。
赵金璇, 王芳, 徐峥嵘, 范怡梅 . 表观遗传调控pre-mRNA的选择性剪接[J]. 遗传, 2014 , 36(3) : 248 -255 . DOI: 10.3724/SP.J.1005.2014.0248
Alternative splicing is a crucial step of the gene expression process in eukaryotes. It is a major cause for protein diversity and plays critical roles in differentiation, development, and disease. The studies on the mechanism of alternative splicing have traditionally focused on RNA sequence elements and their related splicing factors, but recent groundbreaking studies have shown that epigenetic factors play a key role in alternative splicing regulation. DNA methylation, chromatin structure and histone modifications interact with each other and regulate the process of alternative pre-mRNA splicing, forming a large and complex regulatory network. These findings suggest that epigenetic regulation not only determines the initiation of gene expression but also influences the outcome of pre-mRNA splicing. This review mainly focuses on the recent research progress in epigenetic regulation of pre-mRNA alternative splicing, including the functions of DNA methylation, chromatin structure and histone modifications in pre-mRNA alternative splicing, and speculates on its far-reaching effects on the study of human disease.
[1] Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep sur-veying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet, 2008, 40(12): 1413–1415. <\p>
[2] Nilsen TW, Graveley BR. Expansion of the eukaryotic proteome by alternative splicing. Nature, 2010, 463(7280): 457–463. <\p>
[3] Cooper TA, Wan L, Dreyfuss G. RNA and disease. Cell, 2009, 136(4): 777–793. <\p>
[4] Venables JP. Unbalanced alternative splicing and its sig-nificance in cancer. Bioessays, 2006, 28(4): 378–386. <\p>
[5] Keren H, Lev-Maor G, Ast G. Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet, 2010, 11(5): 345–355. <\p>
[6] Barash Y, Calarco JA, Gao W, Pan Q, Wang X, Shai O, Blencowe BJ, Frey BJ. Deciphering the splicing code. Nature, 2010, 465(7294): 53–59. <\p>
[7] Luco RF, Allo M, Schor IE, Kornblihtt AR, Misteli T. Epigenetics in alternative pre-mRNA splicing. Cell, 2011, 144(1): 16–26. <\p>
[8] Han J, Xiong J, Wang D, Fu XD. Pre-mRNA splicing: where and when in the nucleus. Trends Cell Biol, 2011, 21(6): 336–343. <\p>
[9] Moore MJ, Proudfoot NJ. Pre-mRNA processing reaches back to transcription and ahead to translation. Cell, 2009, 136(4): 688–700. <\p>
[10] Bird G, Zorio DA, Bentley DL. RNA polymerase II car-boxy-terminal domain phosphorylation is required for co-transcriptional pre-mRNA splicing and 3'-end formation. Mol Cell Biol, 2004, 24(20): 8963–8969. <\p>
[11] Munoz MJ, de la Mata M, Kornblihtt AR. The carboxy terminal domain of RNA polymerase II and alternative splicing. Trends Biochem Sci, 2010, 35(9): 497–504. <\p>
[12] de la Mata M, Lafaille C, Kornblihtt A R. First come, first served revisited: factors affecting the same alternative splicing event have different effects on the relative rates of intron removal. RNA, 2010, 16(5): 904–912. <\p>
[13] Fong YW, Zhou Q. Stimulatory effect of splicing factors on transcriptional elongation. Nature, 2001, 414(6866): 929–933. <\p>
[14] Lin SR, Coutinho-Mansfield G, Wang D, Pandit S, Fu XD. The splicing factor SC35 has an active role in transcrip-tional elongation. Nat Struct Mol Biol, 2008, 15(8): 819– 826. <\p>
[15] Braunschweig U, Gueroussov S, Plocik AM, Graveley BR, Blencowe BJ. Dynamic integration of splicing within gene regulatory pathways. Cell, 2013, 152(6): 1252–1269. <\p>
[16] Schor IE, Rascovan N, Pelisch F, Allo M, Kornblihtt AR. Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing. Proc Natl Acad Sci USA, 2009, 106(11): 4325–4330. <\p>
[17] Allo M, Buggiano V, Fededa JP, Petrillo E, Schor I, de la Mata M, Agirre E, Plass M, Eyras E, Elela SA, Klinck R, Chabot B, Kornblihtt AR. Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nat Struct Mol Biol, 2009, 16(7): 717–724. <\p>
[18] Batsche E, Yaniv M, Muchardt C. The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol, 2006, 13(1): 22–29. <\p>
[19] Schor IE, Lleres D, Risso GJ, Pawellek A, Ule J, Lamond AI, Kornblihtt AR. Perturbation of chromatin structure globally affects localization and recruitment of splicing factors. PLoS ONE, 2012, 7(11): E48084. <\p>
[20] Schwartz S, Ast G. Chromatin density and splicing destiny: on the cross-talk between chromatin structure and splicing. EMBO J, 2010, 29(10): 1629–1636. <\p>
[21] Spies N, Nielsen CB, Padgett RA, Burge CB. Biased chromatin signatures around polyadenylation sites and exons. Mol Cell, 2009, 36(2): 245–254. <\p>
[22] Tilgner H, Nikolaou C, Althammer S, Sammeth M,
/
| 〈 |
|
〉 |
www.chinagene.cn
备案号：京ICP备09063187号-4
总访问:,今日访问:,当前在线:
