摘要 细胞衰老在表观遗传学上的调控越来越受到人们的关注.Polycomb蛋白复合体(polycomb group proteins)通过对组蛋白的修饰，尤其是甲基化修饰发挥对靶基因的沉默作用，并因此广泛参与到发育、增殖、分化以及肿瘤发生等重要生命过程.目前，有一系列的研究报道了polycomb的各组份参与了细胞衰老的调控.本文对polycomb发挥基因沉默作用机制的最新研究进展进行了归纳总结，并以衰老过程中的重要分子p16为重点，详细介绍了polycomb调节p16表达，影响细胞衰老进程的机制.研究表明，多种polycomb成员同时结合在p16INK4a基因座，它们的结合表现出相互依赖的同时又有各自的作用.这为进一步深入理解细胞衰老提供了表观遗传学的证据.
Abstract：The epigenetic regulation in cellular senescence receives more and more attention. Polycomb group proteins play key roles in gene silencing mediated by histone modification, especially methylation on histone and are invovled in development, proliferation, differeciation and tumour genesis etc. It was reported that many components of the polycomb were involved in the process of senescence. In this review, we summarized the mechanism of polycomb in gene silencing during the cellular senscence and presented the current experimental evidences related to polycomb and senescence, especially on the regulation of p16. Multiple polycomb are accumulated on p16INK4a loci simultaneously in the interdependent manner. They function as a whole complex while individually keep its own effect as well. We are trying to deepen the understanding the mechanism of cellular senescence from epigenetic point of view.
Courtois-Cox S, Jones S L, Cichowski K. Many roads lead to oncogene-induced senescence [J]. Oncogene, 2008, 27(20): 2801-2809
Narita M. Cellular senescence and chromatin organisation [J]. Br J Cancer, 2007, 96(5): 686-691
Herbig U, Jobling W A, Chen B P, et al. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a) [J]. Mol Cell, 2004, 14(4): 501-513
Collado M, Serrano M. Senescence in tumours: evidence from mice and humans[J].Nat Rev Cancer,2010,10 (1): 51-57
Narita M, Lowe S W. Senescence comes of age [J]. Nat Med, 2005, 11(9): 920-922
Lewis E B. A gene complex controlling segmentation in Drosophila[J]. Nature, 1978, 276(5688): 565-570
Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life[J].Nature,2011,469(7330):343- 349
Kaustov L, Ouyang H, Amaya M, et al. Recognition and specificity determinants of the human cbx chromodomains [J]. J Biol Chem, 2011, 286(1): 521-529
Kyba M, Brock H W. The Drosophila polycomb group protein Psc contacts ph and Pc through specific conserved domains [J]. Mol Cell Biol, 1998, 18(5): 2712-2720
Ohta H, Tokimasa S, Zou Z, et al. Structure and chromosomal localization of the RAE28/HPH1 gene, a human homologue of the polyhomeotic gene [J]. DNA Seq, 2000, 11(1-2): 61-73
Satijn D P, Gunster M J, van der Vlag J, et al. RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor [J]. Mol Cell Biol, 1997, 17(7): 4105-4113
Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3 [J]. Curr Opin Genet Dev, 2004, 14(2): 155-164
Montgomery N D, Yee D, Montgomery S A, et al. Molecular and functional mapping of EED motifs required for PRC2-dependent histone methylation [J]. J Mol Biol, 2007, 374(5): 1145-1157
Pasini D, Bracken A P, Jensen M R, et al. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity [J]. EMBO J, 2004, 23(20): 4061-4071
Kuzmichev A, Nishioka K, Erdjument-Bromage H, et al. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein [J]. Genes Dev, 2002, 16(22): 2893-2905
Poux S, Mccabe D, Pirrotta V. Recruitment of components of Polycomb Group chromatin complexes in Drosophila [J]. Development, 2001, 128(1): 75-85
Sing A, Pannell D, Karaiskakis A, et al. A vertebrate Polycomb response element governs segmentation of the posterior hindbrain [J]. Cell, 2009, 138(5): 885-897
Yap K L, Li S, Munoz-Cabello A M, et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a [J]. Mol Cell, 2010, 38(5): 662- 674
Ebert A, Lein S, Schotta G, et al. Histone modification and the control of heterochromatic gene silencing in Drosophila [J]. Chromosome Res, 2006, 14(4): 377-392
Sykes D B, Kamps M P. Estrogen-dependent E2a/Pbx1 myeloid cell lines exhibit conditional differentiation that can be arrested by other leukemic oncoproteins [J]. Blood, 2001, 98(8): 2308-2318
Caretti G, Di Padova M, Micales B, et al. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation [J]. Genes Dev, 2004, 18(21): 2627-2638
Herranz N, Pasini D, Diaz V M, et al. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor [J]. Mol Cell Biol, 2008, 28(15): 4772-4781
Hung T, Chang H Y. Long noncoding RNA in genome regulation: prospects and mechanisms [J]. RNA Biol, 2010, 7(5): 582-585
Niinuma T, Suzuki H, Nojima M, et al. Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors [J]. Cancer Res, 2012,72(5):1126-1136
Kogo R, Shimamura T, Mimori K, et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers [J]. Cancer Res, 2011, 71(20): 6320-6326
Yang Z, Zhou L, Wu L M, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation[J]. Ann Surg Oncol, 2011,18(5): 1243-1250
Gupta R A, Shah N, Wang K C, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis [J]. Nature, 2010, 464(7291): 1071-1076
Creyghton M P, Markoulaki S, Levine S S, et al. H2AZ is enriched at polycomb complex target genes in ES cells and is necessary for lineage commitment [J]. Cell, 2008, 135(4): 649-661
Buschbeck M, Uribesalgo I, Wibowo I, et al. The histone variant macroH2A is an epigenetic regulator of key developmental genes [J]. Nat Struct Mol Biol, 2009, 16(10): 1074-1079
Bracken A P, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells [J]. Genes Dev, 2007, 21(5): 525-530
Vire E, Brenner C, Deplus R, et al. The Polycomb group protein EZH2 directly controls DNA methylation [J]. Nature, 2006, 439(7078): 871-874
Wong C M, Wong C C, Ng Y L, et al. Transcriptional repressive H3K9 and H3K27 methylations contribute to DNMT1-mediated DNA methylation recovery [J]. PLoS One, 2011, 6(2): e16702
Stock J K, Giadrossi S, Casanova M, et al. Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells [J]. Nat Cell Biol, 2007, 9(12): 1428-1435
Zhou W, Zhu P, Wang J, et al. Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation [J]. Mol Cell, 2008, 29(1): 69-80
Pasini D, Malatesta M, Jung H R, et al. Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes [J]. Nucleic Acids Res, 2010, 38(15): 4958-4969
Smith E R, Lee M G, Winter B, et al. Drosophila UTX is a histone H3 Lys27 demethylase that colocalizes with the elongating form of RNA polymerase II [J]. Mol Cell Biol, 2008, 28(3): 1041-1046
Lee M G, Norman J, Shilatifard A, et al. Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein [J]. Cell, 2007, 128(5): 877-887
Reff M, Schneider E L. Cell culture aging [J]. Mol Cell Biochem, 1981, 36(3): 169-176
Giacinti C, Giordano A. RB and cell cycle progression [J]. Oncogene, 2006, 25(38): 5220-5227
Adams P D. Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging [J].Gene, 2007, 397(1-2): 84-93
Agherbi H, Gaussmann-Wenger A, Verthuy C, et al. Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence [J]. PLoS One, 2009, 4(5): e5622
Maertens G N, El Messaoudi-Aubert S, Racek T, et al. Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus [J]. PLoS One, 2009, 4(7): e6380
Pasini D, Bracken A P, Helin K. Polycomb group proteins in cell cycle progression and cancer [J]. Cell Cycle, 2004, 3(4): 396-400
Bracken A P, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells [J]. Genes Dev, 2007, 21(5): 525-530
Guo W J, Datta S, Band V, et al. Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi-1 and c-Myc oncoproteins [J]. Mol Biol Cell, 2007, 18(2): 536-546
Gil J, Bernard D, Martinez D, et al. Polycomb CBX7 has a unifying role in cellular lifespan [J]. Nat Cell Biol, 2004, 6(1): 67-72
Dietrich N, Bracken A P, Trinh E, et al. Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus [J]. EMBO J, 2007, 26(6): 1637-1648
Maertens G N, El Messaoudi-Aubert S, Racek T, et al. Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus [J]. PLoS One, 2009, 4(7): e6380
Ciarapica R, Miele L, Giordano A, et al. Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications [J]. BMC Med, 2011, 9: 63
Chen H, Gu X, Su I H, et al. Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus [J]. Genes Dev, 2009, 23(8): 975-985
Pasini D, Bracken A P, Jensen M R, et al. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity [J]. EMBO J, 2004, 23(20): 4061-4071
