Function of Polycomb repressive complexes in stem cells

Abstract

Stem cells are unique cell populations identified in a variety of normal tissues and some cancers. Maintenance of stem cell pools is essential for normal development, tissue homeostasis, and tumorigenesis. Recent studies have revealed that Polycomb repressive complexes (PRCs) play a central role in maintaining stem cells by repressing cellular senescence and differentiation. Here, we will review recent findings on dynamic composition of PRC complexes and sub-complexes, how PRCs are recruited to chromatin, and their functional roles in maintaining self-renewal of stem cells. Furthermore, we will discuss how PRCs, CpG islands (CGIs), the INK4A/ARF/INK4B locus, and developmental genes form a hierarchical regulatory axis that is utilized by a variety of stem cells to maintain their self-renewal and identities.

Keywords

Polycomb repressive complexes / gene silencing / CpG islands / stem cells / self-renewal

References

[1] Abraham B J, Cui K, Tang Q, Zhao K (2013). Dynamic regulation of epigenomic landscapes during hematopoiesis. BMC Genomics, 14(1): 193

[2] Ballare C, Lange M, Lapinaite A, Martin G M, Morey L, Pascual G, Liefke R, Simon B, Shi Y, Gozani O, Carlomagno T, Benitah S A, Di Croce L (2012). Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity. Nat Struct Mol Biol, 19(12): 1257–1265

[3] Bernstein B E, Mikkelsen T S, Xie X, Kamal M, Huebert D J, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber S L, Lander E S (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 125(2): 315–326

[4] Blackledge N P, Farcas A M, Kondo T, King H W, McGouran J F, Hanssen L L, Ito S, Cooper S, Kondo K, Koseki Y, Ishikura T, Long H K, Sheahan T W, Brockdorff N, Kessler B M, Koseki H, Klose R J (2014). Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell, 157(6): 1445–1459

[5] Cai L, Rothbart S B, Lu R, Xu B, Chen W Y, Tripathy A, Rockowitz S, Zheng D, Patel D J, Allis C D, Strahl B D, Song J, Wang G G (2013). An H3K36 methylation-engaging Tudor motif of polycomb-like proteins mediates PRC2 complex targeting. Mol Cell, 49(3): 571–582

[6] Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones R S, Zhang Y (2002). Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science, 298(5595): 1039–1043

[7] Chan C S, Rastelli L, Pirrotta V (1994). A Polycomb response element in the Ubx gene that determines an epigenetically inherited state of repression. EMBO J, 13: 2553–2564

[8] Cui K, Zang C, Roh T Y, Schones D E, Childs R W, Peng W, Zhao K (2009). Chromatin signatures inmultipotent humanhematopoietic stem cells indicatethefate of bivalent genes during differentiation. Cell Stem Cell, 4(1): 80–93

[9] Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V (2002). Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell, 111(2): 185–196

[10] de Napoles M, Mermoud J E, Wakao R, Tang Y A, Endoh M, Appanah R, Nesterova T B, Silva J, Otte A P, Vidal M, Koseki H, Brockdorff N (2004). Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell, 7(5): 663–676

[11] Deaton A M, Bird A (2011). CpG islands and the regulation of transcription. Genes Dev, 25(10): 1010–1022

[12] Dietrich N, Lerdrup M, Landt E, Agrawal-Singh S, Bak M, Tommerup N, Rappsilber J, Sodersten E, Hansen K (2012). REST-mediated recruitment of polycomb repressor complexes in mammalian cells. PLoS Genet, 8(3): e1002494

[13] Endoh M, Endo T A, Endoh T, Isono K, Sharif J, Ohara O, Toyoda T, Ito T, Eskeland R, Bickmore W A, Vidal M, Bernstein B E, Koseki H (2012). Histone H2A mono-ubiquitination is a crucial step to mediate PRC1-dependent repression of developmental genes to maintain ES cell identity. PLoS Genet, 8(7): e1002774

[14] Eskeland R, Freyer E, Leeb M, Wutz A, Bickmore W A (2010a). Histone acetylation and the maintenance of chromatin compaction by Polycomb repressive complexes. Cold Spring Harb Symp Quant Biol, 75(0): 71–78

[15] Eskeland R, Leeb M, Grimes G R, Kress C, Boyle S, Sproul D, Gilbert N, Fan Y, Skoultchi A I, Wutz A, Bickmore W A (2010b). Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. Mol Cell, 38(3): 452–464

[16] Evans M J, Kaufman M H (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819): 154–156

[17] Farcas A M, Blackledge N P, Sudbery I, Long H K, McGouran J F, Rose N R, Lee S, Sims D, Cerase A, Sheahan T W, Koseki H, Brockdorff N, Ponting C P, Kessler B M, Klose R J (2012). KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands. eLife, 1: e00205

[18] Fischle W, Wang Y, Jacobs S A, Kim Y, Allis C D, Khorasanizadeh S (2003). Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev, 17(15): 1870–1881

[19] Gao Z, Lee P, Stafford J M, von Schimmelmann M, Schaefer A, Reinberg D (2014). An AUTS2-Polycomb complex activates gene expression in the CNS. Nature, 516(7531): 349–354

[20] Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D (2012). PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol Cell, 45(3): 344–356

[21] Gaytan de Ayala Alonso A, Gutierrez L, Fritsch C, Papp B, Beuchle D, Muller J (2007). A genetic screen identifies novel polycomb group genes in <?Pub Caret?>Drosophila. Genetics, 176(4): 2099–2108

[22] Grau D J, Antao J M, Kingston R E (2010). Functional dissection of Polycomb repressive complex 1 reveals the importance of a charged domain. Cold Spring Harb Symp Quant Biol, 75(0): 61–70

[23] He J, Kallin E M, Tsukada Y, Zhang Y (2008). The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b). Nat Struct Mol Biol, 15(11): 1169–1175

[24] He J, Nguyen A T, Zhang Y (2011). KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. Blood, 117(14): 3869–3880

[25] He J, Shen L, Wan M, Taranova O, Wu H, Zhang Y (2013). Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat Cell Biol, 15(4): 373–384

[26] Hidalgo I, Herrera-Merchan A, Ligos J M, Carramolino L, Nunez J, Martinez F, Dominguez O, Torres M, Gonzalez S (2012). Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. Cell Stem Cell, 11(5): 649–662

[27] Jiao L, Liu X (2015). Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science, 350(6258): aac4383

[28] Kim H, Kang K, Kim J (2009). AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2. Nucleic Acids Res, 37(9): 2940–2950

[29] Kim W Y, Sharpless N E (2006). The regulation of INK4/ARF in cancer and aging. Cell, 127(2): 265–275

[30] Klauke K, Radulovic V, Broekhuis M, Weersing E, Zwart E, Olthof S, Ritsema M, Bruggeman S, Wu X, Helin K, Bystrykh L, de Haan G (2013). Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat Cell Biol, 15(4): 353–362

[31] Kreso A, Dick J E (2014). Evolution of the cancer stem cell model. Cell Stem Cell, 14(3): 275–291

[32] Ku M, Koche R P, Rheinbay E, Mendenhall E M, Endoh M, Mikkelsen T S, Presser A, Nusbaum C, Xie X, Chi A S, Adli M, Kasif S, Ptaszek L M, Cowan C A, Lander E S, Koseki H, Bernstein B E (2008). Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet, 4(10): e1000242

[33] Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D (2002). Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev, 16(22): 2893–2905

[34] Lessard J, Sauvageau G (2003). Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature, 423(6937): 255–260

[35] Lewis E B (1978). A gene complex controlling segmentation in Drosophila. Nature, 276(5688): 565–570

[36] Li G, Margueron R, Ku M, Chambon P, Bernstein B E, Reinberg D (2010). Jarid2 and PRC2, partners in regulating gene expression. Genes Dev, 24(4): 368–380

[37] Liang G, He J, Zhang Y (2012). Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat Cell Biol, 14(5): 457–466

[38] Long H K, Blackledge N P, Klose R J (2013). ZF-CxxC domain-containing proteins, CpG islands and the chromatin connection. Biochem Soc Trans, 41(3): 727–740

[39] Luis N M, Morey L, Di Croce L, Benitah S A (2012). Polycomb in stem cells: PRC1 branches out. Cell Stem Cell, 11(1): 16–21

[40] Martin G R (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA, 78(12): 7634–7638

[41] Mendenhall E M, Koche R P, Truong T, Zhou V W, Issac B, Chi A S, Ku M, Bernstein B E (2010). GC-rich sequence elements recruit PRC2 in mammalian ES cells. PLoS Genet, 6(12): e1001244

[42] Mikkelsen T S, Ku M, Jaffe D B, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim T K, Koche R P, Lee W, Mendenhall E, O’Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander E S, Bernstein B E (2007). Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature, 448(7153): 553–560

[43] Min J, Zhang Y, Xu R M (2003). Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev, 17(15): 1823–1828

[44] Mochizuki-Kashio M, Mishima Y, Miyagi S, Negishi M, Saraya A, Konuma T, Shinga J, Koseki H, Iwama A (2011). Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood, 118(25): 6553–6561

[45] Mohd-Sarip A, Cleard F, Mishra R K, Karch F, Verrijzer C P (2005). Synergistic recognition of an epigenetic DNA element by Pleiohomeotic and a Polycomb core complex. Genes Dev, 19(15): 1755–1760

[46] Mohd-Sarip A, Venturini F, Chalkley G E, Verrijzer C P (2002). Pleiohomeotic can link polycomb to DNA and mediate transcriptional repression. Mol Cell Biol, 22(21): 7473–7483

[47] Molofsky A V, He S, Bydon M, Morrison S J, Pardal R (2005). Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev, 19(12): 1432–1437

[48] Molofsky A V, Pardal R, Iwashita T, Park I K, Clarke M F, Morrison S J (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature, 425(6961): 962–967

[49] Muller J, Hart C M, Francis N J, Vargas M L, Sengupta A, Wild B, Miller E L, O'Connor M B, Kingston R E, Simon J A (2002). Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell, 111(2): 197–208

[50] Nusslein-Volhard C, Kluding H, Jurgens G (1985). Genes affecting the segmental subdivision of the Drosophila embryo. Cold Spring Harb Symp Quant Biol, 50(0): 145–154

[51] Onder T T, Kara N, Cherry A, Sinha A U, Zhu N, Bernt K M, Cahan P, Marcarci B O, Unternaehrer J, Gupta P B, Lander E S, Armstrong S A, Daley G Q (2012). Chromatin-modifying enzymes as modulators of reprogramming. Nature, 483(7391): 598–602

[52] Park I K, Qian D, Kiel M, Becker M W, Pihalja M, Weissman I L, Morrison S J, Clarke M F (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature, 423(6937): 302–305

[53] Pasini D, Bracken A P, Hansen J B, Capillo M, Helin K (2007). The polycomb group protein Suz12 is required for embryonic stemcell differentiation. Mol Cell Biol, 27(10): 3769–3779

[54] Pasini D, Cloos P A, Walfridsson J, Olsson L, Bukowski J P, Johansen J V, Bak M, Tommerup N, Rappsilber J, Helin K (2010). JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature, 464(7286): 306–310

[55] Pereira J D, Sansom S N, Smith J, Dobenecker M W, Tarakhovsky A, Livesey F J (2010). Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci USA, 107(36): 15957–15962

[56] Pfau R, Tzatsos A, Kampranis S C, Serebrennikova O B, Bear S E, Tsichlis P N (2008). Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via aJmjC domain-dependent process. Proc Natl Acad Sci USA, 105(6): 1907–1912

[57] Poux S, Melfi R, Pirrotta V (2001). Establishment of Polycomb silencing requires a transient interaction between PC and ESC. Genes Dev, 15(19): 2509–2514

[58] Ren X, Kerppola T K (2011). REST interacts with Cbx proteins and regulates polycomb repressive complex 1 occupancy at RE1 elements. Mol Cell Biol, 31(10): 2100–2110

[59] Riising E M, Comet I, Leblanc B, Wu X, Johansen J V, Helin K (2014). Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol Cell, 55(3): 347–360

[60] Rinn J L, Kertesz M, Wang J K, Squazzo S L, Xu X, Brugmann S A, Goodnough L H, Helms J A, Farnham P J, Segal E, Chang H Y (2007). Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell, 129(7): 1311–1323

[61] Roman-Trufero M, Mendez-Gomez H R, Perez C, Hijikata A, Fujimura Y, Endo T, Koseki H, Vicario-Abejon C, Vidal M (2009). Maintenance of undifferentiated state and self-renewal of embryonic neural stem cells by Polycomb protein Ring1B. Stem Cells, 27(7): 15591570

[62] Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J, Bezstarosti K, Taylor S, Ura H, Koide H, Wutz A, Vidal M, Elderkin S, Brockdorff N (2012). RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell, 148(4): 664–678

[63] Thornton S R, Butty V L, Levine S S, Boyer L A (2014). Polycomb Repressive Complex 2 regulates lineage fidelity during embryonic stem cell differentiation. PLoS ONE, 9(10): e110498

[64] Ueda K, Yoshimi A, Kagoya Y, Nishikawa S, Marquez V E, Nakagawa M, Kurokawa M (2014). Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16. Cancer Sci, 105: 512–519

[65] Utikal J, Polo J M, Stadtfeld M, Maherali N, Kulalert W, Walsh R M, Khalil A, Rheinwald J G, Hochedlinger K (2009). Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature, 460(7259): 1145–1148

[66] van den Boom V, Rozenveld-Geugien M, Bonardi F, Malanga D, van Gosliga D, Heijink A M, Viglietto G, Morrone G, Fusetti F, Vellenga E, Schuringa J J (2013). Nonredundant and locus-specific gene repression functions of PRC1 paralog family members in human hematopoietic stem/progenitor cells. Blood, 121(13): 2452–2461

[67] van der Stoop P, Boutsma E A, Hulsman D, Noback S, Heimerikx M, Kerkhoven R M, Voncken J W, Wessels L F, van Lohuizen M (2008). Ubiquitin E3 ligase Ring1b/Rnf2 of polycomb repressive complex 1 contributes to stable maintenance of mouse embryonic stem cells. PLoS ONE, 3(5): e2235

[68] Walker E, Chang W Y, Hunkapiller J, Cagney G, Garcha K, Torchia J, Krogan N J, Reiter J F, Stanford W L (2010). Polycomb-like 2 associates with PRC2 and regulates transcriptional networks during mouse embryonic stem cell self-renewal and differentiation. Cell Stem Cell, 6(2): 153–166

[69] Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones R S, Zhang Y (2004a). Role of histone H2A ubiquitination in Polycomb silencing. Nature, 431(7010): 873–878

[70] Wang L, Brown J L, Cao R, Zhang Y, Kassis J A, Jones R S (2004b). Hierarchical recruitment of polycomb group silencing complexes. Mol Cell, 14(5): 637–646

[71] Woo C J, Kharchenko P V, Daheron L, Park P J, Kingston R E (2010). A region of the human HOXD cluster that confers polycomb-group responsiveness. Cell, 140(1): 99–110

[72] Wu X, Johansen J V, Helin K (2013). Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol Cell, 49(6): 1134–1146

[73] Xie H, Xu J, Hsu J H, Nguyen M, Fujiwara Y, Peng C, Orkin S H (2014). Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell, 14(1): 68–80

[74] Xu B, On D M, Ma A, Parton T, Konze K D, Pattenden S G, Allison D F, Cai L, Rockowitz S, Liu S, Liu Y, Li F, Vedadi M, Frye S V, Garcia B A, Zheng D, Jin J, Wang G G (2015). Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood, 125(2): 346–357

[75] Xu K, Wu Z J, Groner A C, He H H, Cai C, Lis R T, Wu X, Stack E C, Loda M, Liu T, Xu H, Cato L, Thornton J E, Gregory R I, Morrissey C, Vessella R L, Montironi R, Magi-Galluzzi C, Kantoff P W, Balk S P, Liu X S, Brown M (2012). EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science, 338(6113): 1465–1469

[76] Ying Q L, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A (2008). The ground state of embryonic stem cell self-renewal. Nature, 453(7194): 519–523

[77] Yu M, Mazor T, Huang H, Huang H T, Kathrein K L, Woo A J, Chouinard C R, Labadorf A, Akie T E, Moran T B, Xie H, Zacharek S, Taniuchi I, Roeder R G, Kim C F, Zon L I, Fraenkel E, Cantor A B (2012). Direct recruitment of polycomb repressive complex 1 to chromatin by core binding transcription factors. Mol Cell, 45(3): 330–343

[78] Yuan J, Takeuchi M, Negishi M, Oguro H, Ichikawa H, Iwama A (2011). Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells. Leukemia, 25(8): 1335–1343

[79] Zhang Z, Jones A, Sun C W, Li C, Chang C W, Joo H Y, Dai Q, Mysliwiec M R, Wu L C, Guo Y, Yang W, Liu K, Pawlik K M, Erdjument-Bromage H, Tempst P, Lee Y, Min J, Townes T M, Wang H (2011). PRC2 complexes with JARID2, MTF2, and esPRC2p48 in ES cells to modulate ES cell pluripotency and somatic cell reprogramming. Stem Cells, 29(2): 229–240

[80] Zhao J, Sun B K, Erwin J A, Song J J, Lee J T (2008). Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science, 322(5902): 750–756

Compliance with ethics guidelines

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg