PcG家族CBX2基因的发现及其在哺乳动物性发育中的作用
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摘要
Polycomb group complex (PcG)作为发挥转录抑制作用的重要表观遗传调控复合物参与发育、衰老以及肿瘤发生等重要生理过程。Pc G家族成员,包括PRC1 (Polycomb repressive complex 1)与PRC2 (Polycomb repressive complex 2)两种复合物,各组分间功能既协同,又不失特性,色素框同源蛋白(Chromobox homolog CBX)是PRC1的主要核心蛋白,其家族的成员之一CBX2近年来成为研究的热点。本研究综述了CBX2基因的发现、基因和蛋白质的结构组成及其在人和鼠不同组织的表达情况,阐述了CBX2在哺乳动物性发育中的作用及研究进展,发现CBX2除参与PcG复合体发挥转录抑制作用外,还具有基因转录激活作用,它作为哺乳动物性别决定级联中SRY (Sex region of Y chromosome)的上游基因可直接激活靶基因SF1/NR5A1的表达,如果CBX2基因突变或缺失将使雄性小鼠发生性反转,在人类中造成46,XY性发育障碍(disorders of sex development, DSD),为进一步研究CBX2基因在动物性发育调控中的作用提供依据。
Polycomb group(Pc G), as a key epigenetic regulatory complex, plays a role in inhibiting transcription and is involved in a diverse range of processes such as development, senescence and tumorigenesis, etc. PcG consists of two complexes, PRC1(Polycomb repressive complex 1) and PRC2(Polycomb repressive complex 2), in which each component coordinates but presents distinct function. Chromobox homolog(CBX) is the major core protein of PRC1,and one of its family members, CBX2, has become a hot topic recently. This review summarized the discovery of CBX2, the structural composition of genes and proteins, and its expression in different tissues of human and mouse,and expounded the role of CBX2 in sexual development of mammalian and the research progress. It was found that in addition to participating in the PcG complex to inhibit transcription, CBX2 also played a role of gene transcriptional activation. As the upstream gene of SRY(Sex region of Y chromosome) in sex determination cascade of mammalian, CBX2 could directly activate the expression of target gene, SF1/NR5 A1. If the CBX2 gene was mutated or deleted, it would cause sexual reversal in male mice, and 46 XY DSD(disorders of sex development) in humans. These might provide a basis for further exploraton of the role of the CBX2 in animal sexual development regulation.
Polycomb group(Pc G), as a key epigenetic regulatory complex, plays a role in inhibiting transcription and is involved in a diverse range of processes such as development, senescence and tumorigenesis, etc. PcG consists of two complexes, PRC1(Polycomb repressive complex 1) and PRC2(Polycomb repressive complex 2), in which each component coordinates but presents distinct function. Chromobox homolog(CBX) is the major core protein of PRC1,and one of its family members, CBX2, has become a hot topic recently. This review summarized the discovery of CBX2, the structural composition of genes and proteins, and its expression in different tissues of human and mouse,and expounded the role of CBX2 in sexual development of mammalian and the research progress. It was found that in addition to participating in the PcG complex to inhibit transcription, CBX2 also played a role of gene transcriptional activation. As the upstream gene of SRY(Sex region of Y chromosome) in sex determination cascade of mammalian, CBX2 could directly activate the expression of target gene, SF1/NR5 A1. If the CBX2 gene was mutated or deleted, it would cause sexual reversal in male mice, and 46 XY DSD(disorders of sex development) in humans. These might provide a basis for further exploraton of the role of the CBX2 in animal sexual development regulation.
引文
Alkema M.J.,Bronk M.,Verhoeven E.,Otte A.,Veer L.J.,Berns A.,and Lohuizen M.,1997,Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex,Genes&Development,11(2):226-240
Baumann C.,De L.,and Fuente R.,2011,Role of polycomb group protein CBX2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline,Genes,2(1):59-80
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.,and Lander E.S.,2006,A bivalent chromatin structure marks key developmental genes in embryonic stem cells,Cell,125(2):315-326
Biason-Lauber A.,Konrad D.,Meyer M.,Debeaufort C.,and Schoenle E.J.,2009,Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene,The American Journal of Human Genetics,84(5):658-663
Clermont P.L.,Sun L.,Crea F.,Thu K.L.,Zhang A.,Parolia A.,Lam W.L.,and Helgason C.D.,2014,Genotranscriptomic meta-analysis of the Polycomb gene CBX2 in human cancers:initial evidence of an oncogenic role,British Journal of Cancer,111(8):1663-1672
Decamillis M.,Cheng N.S.,Pierre D.,and Brock H.W.,1992,The polyhomeotic gene of Drosophila encodes a chromatin protein that shares polytene chromosome-binding sites with Polycomb,Genes&Development,6(2):223-232
Eid W.,Opitz L.,and Biason-Lauber A.,2015,Genomewide identification of CBX2 targets:insights in the human sex development network,Molcular Endocrinology,29(2):247-257
Fauvarque M.O.,Zuber V.,and Dura J.M.,1995,Regulation of polyhomeotic transcription may involve local changes in chromatin activity in Drosophila,Mechanisms Development,52(2-3):343-355
Gao Z.,Zhang J.,Bonasio R.,Strino F.,Sawai A.,Parisi F.,Kluger Y.,and Reinberg D.,2012,PCGF homologs,CBXproteins,and RYBP define functionally distinct PRC1 family complexes,Molecular Cell,45(3):344-356
Hatano A.,Matsumoto M.,Higashinakagawa T.,and Nakayama K.I.,2010,Phosphorylation of the chromodomain changes the binding specificity of CBX2 for methylated histone H3,Biochemical and Biophysical Reserch Communication,397(1):93-99
Hirose S.,Komoike Y.,and Higashinakagawa T.,2006,Identification of a nuclear localization signal in mouse polycomb protein,M33,Zoological Science,23(9):785-791
Katoh-Fukui Y.,Owaki A.,Toyama Y.,Kusaka M.,Shinohara Y.,Maekawa M.,Toshimori K.,and Morohashi K.,2005,Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression,Blood,106(5):1612-1620
Katoh-Fukui Y.,Tsuchiya R.,Shiroishi T.,Nakahara Y.,Hashimoto N.,Noguchi K.,and Higashinakagawa T.,1998,Male-to-female sex reversal in M33 mutant mice,Nature,393(6686):688-692
Lajeunesse D.,and Shearn A.,1996,E(z):a polycomb group gene or a trithorax group gene,Development,122(7):2189-2197
Lewis E.B.,1978,A gene complex controlling segmentation in Drosophila,Nature,276(5688):565-570
Luis N.M.,Morey L.,Mejetta S.,Pascual G.,Janich P.,Kuebler B.,Cozutto L.,Roma G.,Nascimento E.,Frye M.,Croce L.D.,and Benitah S.A.,2011,Regulation of human epidermal stem cell proliferation and senescence requires polycombdependent and-independent functions of Cbx4,Cell Stem Cell,9(3):233-246
Ma R.G.,Zhang Y.,Sun T.T.,and Cheng B.,2014,Epigenetic regulation by polycomb group complexes:focus on roles of CBX proteins,Journal of Zhejiang University Science B:Biomedicine&Biotechnology,15(5):412-428
Margueron R.,and Reinberg D.,2011,The Polycomb complex PRC2 and its mark in life,Nature,469(7330):343-349
Milne T.A.,Sinclair D.A.,and Brock H.W.,1999,The Additional sex combs gene of Drosophila is required for activation and repression of homeotic loci,and interacts specifically with Polycomb and super sex combs,Molecular&General Genetics,261(4-5):753-761
Morey L.,Pascual G.,Cozzuto L.,Roma G.,Wutz A.,Benitah S.A.,and Di Croce L.,2012,Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells,Cell Stem Cell,10(1):47-62
Noguchi K.,Shiurba R.,and Higashinakagawa T.,2002,Nuclear translocation of mouse polycomb m33 protein in regenerating liver,Biochemical and Biophysical Research Communications,291(3):508-515
O'loghlen A.,Munozcabello A.M.,Gasparmaia A.,Wu H.A.,Banito A.,Kunowska N.,Racek T.,Pemberton H.N.,Beolchi P.,Lavial F.,Masui O.,Vermeulen M.,Carroll T.,Graumann J.,Heard E.,Dillon N.,Azuara V.,Snijders A.P.,Peters G.,Bernstein E.,and Gil J.,2012,MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation,Cell Stem Cell,10(1):33-46
O'Mahony D.J.,Smith S.D.,Xie W.Q.,and Rothblum L.I.,1992,Analysis of the phosphorylation,DNA-binding and dimerization properties of the RNA polymerase I transcription factors UBF1 and UBF2,Nucleic Acids Research,20(6):1301-1308
Rajasekhar V.K.,and Begemann M.,2007,Concise review:roles of polycomb group proteins in development and disease:a stem cell perspective,Stem Cells,25(10):2498-2510
Sauvageau M.,and Sauvageau G.,2010,Polycomb group proteins:multi-faceted regulators of somatic stem cells and cancer,Cell Stem Cell,7(3):299-313
Scelfo A.,Piunti A.,and Pasini D.,2015,The controversial role of the Polycomb group proteins in transcription and cancer:how much do we not understand Polycomb proteins,The FEBS Journal,282(9):1703-1722
Senthilkumar R.,and Mishra R.K.,2009,Novel motifs distinguish multiple homologues of Polycomb in vertebrates:expansion and diversification of the epigenetic toolkit,BMCGenomics,10(1):549
Shirai M.,Osugi T.,Koga H.,Kaji Y.,Takimoto E.,Komuro I.,Hara J.,Miwa T.,Yamauchi-Takihara K.,and Takihara Y.,2002,The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis,The Journal of Clinical Investigation,110(2):177-184
Simon J.A.,and Kingston R.E.,2009,Mechanisms of polycomb gene silencing:knowns and unknowns,Nature Reviews Molecular Cell Biology,10(10):697-708
Surface L.E.,Thornton S.R.,and Boyer L.A.,2010,Polycomb group proteins set the stage for early lineage commitment,Cell Stem Cell,7(3):288-298
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.,and Brockdorff N.,2012,RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3,Cell,148(4):664-678
Zeng K.,and Liu M.,2017,Research progress of CBX protein and tumor,Shiyong Zhongliuxue Zazhi(Journal of Practical Oncology),31(2):165-169(曾凯,刘明,2017,CBX与肿瘤关系的研究进展,实用肿瘤学杂志,31(2):165-169)
Baumann C.,De L.,and Fuente R.,2011,Role of polycomb group protein CBX2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline,Genes,2(1):59-80
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.,and Lander E.S.,2006,A bivalent chromatin structure marks key developmental genes in embryonic stem cells,Cell,125(2):315-326
Biason-Lauber A.,Konrad D.,Meyer M.,Debeaufort C.,and Schoenle E.J.,2009,Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene,The American Journal of Human Genetics,84(5):658-663
Clermont P.L.,Sun L.,Crea F.,Thu K.L.,Zhang A.,Parolia A.,Lam W.L.,and Helgason C.D.,2014,Genotranscriptomic meta-analysis of the Polycomb gene CBX2 in human cancers:initial evidence of an oncogenic role,British Journal of Cancer,111(8):1663-1672
Decamillis M.,Cheng N.S.,Pierre D.,and Brock H.W.,1992,The polyhomeotic gene of Drosophila encodes a chromatin protein that shares polytene chromosome-binding sites with Polycomb,Genes&Development,6(2):223-232
Eid W.,Opitz L.,and Biason-Lauber A.,2015,Genomewide identification of CBX2 targets:insights in the human sex development network,Molcular Endocrinology,29(2):247-257
Fauvarque M.O.,Zuber V.,and Dura J.M.,1995,Regulation of polyhomeotic transcription may involve local changes in chromatin activity in Drosophila,Mechanisms Development,52(2-3):343-355
Gao Z.,Zhang J.,Bonasio R.,Strino F.,Sawai A.,Parisi F.,Kluger Y.,and Reinberg D.,2012,PCGF homologs,CBXproteins,and RYBP define functionally distinct PRC1 family complexes,Molecular Cell,45(3):344-356
Hatano A.,Matsumoto M.,Higashinakagawa T.,and Nakayama K.I.,2010,Phosphorylation of the chromodomain changes the binding specificity of CBX2 for methylated histone H3,Biochemical and Biophysical Reserch Communication,397(1):93-99
Hirose S.,Komoike Y.,and Higashinakagawa T.,2006,Identification of a nuclear localization signal in mouse polycomb protein,M33,Zoological Science,23(9):785-791
Katoh-Fukui Y.,Owaki A.,Toyama Y.,Kusaka M.,Shinohara Y.,Maekawa M.,Toshimori K.,and Morohashi K.,2005,Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression,Blood,106(5):1612-1620
Katoh-Fukui Y.,Tsuchiya R.,Shiroishi T.,Nakahara Y.,Hashimoto N.,Noguchi K.,and Higashinakagawa T.,1998,Male-to-female sex reversal in M33 mutant mice,Nature,393(6686):688-692
Lajeunesse D.,and Shearn A.,1996,E(z):a polycomb group gene or a trithorax group gene,Development,122(7):2189-2197
Lewis E.B.,1978,A gene complex controlling segmentation in Drosophila,Nature,276(5688):565-570
Luis N.M.,Morey L.,Mejetta S.,Pascual G.,Janich P.,Kuebler B.,Cozutto L.,Roma G.,Nascimento E.,Frye M.,Croce L.D.,and Benitah S.A.,2011,Regulation of human epidermal stem cell proliferation and senescence requires polycombdependent and-independent functions of Cbx4,Cell Stem Cell,9(3):233-246
Ma R.G.,Zhang Y.,Sun T.T.,and Cheng B.,2014,Epigenetic regulation by polycomb group complexes:focus on roles of CBX proteins,Journal of Zhejiang University Science B:Biomedicine&Biotechnology,15(5):412-428
Margueron R.,and Reinberg D.,2011,The Polycomb complex PRC2 and its mark in life,Nature,469(7330):343-349
Milne T.A.,Sinclair D.A.,and Brock H.W.,1999,The Additional sex combs gene of Drosophila is required for activation and repression of homeotic loci,and interacts specifically with Polycomb and super sex combs,Molecular&General Genetics,261(4-5):753-761
Morey L.,Pascual G.,Cozzuto L.,Roma G.,Wutz A.,Benitah S.A.,and Di Croce L.,2012,Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells,Cell Stem Cell,10(1):47-62
Noguchi K.,Shiurba R.,and Higashinakagawa T.,2002,Nuclear translocation of mouse polycomb m33 protein in regenerating liver,Biochemical and Biophysical Research Communications,291(3):508-515
O'loghlen A.,Munozcabello A.M.,Gasparmaia A.,Wu H.A.,Banito A.,Kunowska N.,Racek T.,Pemberton H.N.,Beolchi P.,Lavial F.,Masui O.,Vermeulen M.,Carroll T.,Graumann J.,Heard E.,Dillon N.,Azuara V.,Snijders A.P.,Peters G.,Bernstein E.,and Gil J.,2012,MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation,Cell Stem Cell,10(1):33-46
O'Mahony D.J.,Smith S.D.,Xie W.Q.,and Rothblum L.I.,1992,Analysis of the phosphorylation,DNA-binding and dimerization properties of the RNA polymerase I transcription factors UBF1 and UBF2,Nucleic Acids Research,20(6):1301-1308
Rajasekhar V.K.,and Begemann M.,2007,Concise review:roles of polycomb group proteins in development and disease:a stem cell perspective,Stem Cells,25(10):2498-2510
Sauvageau M.,and Sauvageau G.,2010,Polycomb group proteins:multi-faceted regulators of somatic stem cells and cancer,Cell Stem Cell,7(3):299-313
Scelfo A.,Piunti A.,and Pasini D.,2015,The controversial role of the Polycomb group proteins in transcription and cancer:how much do we not understand Polycomb proteins,The FEBS Journal,282(9):1703-1722
Senthilkumar R.,and Mishra R.K.,2009,Novel motifs distinguish multiple homologues of Polycomb in vertebrates:expansion and diversification of the epigenetic toolkit,BMCGenomics,10(1):549
Shirai M.,Osugi T.,Koga H.,Kaji Y.,Takimoto E.,Komuro I.,Hara J.,Miwa T.,Yamauchi-Takihara K.,and Takihara Y.,2002,The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis,The Journal of Clinical Investigation,110(2):177-184
Simon J.A.,and Kingston R.E.,2009,Mechanisms of polycomb gene silencing:knowns and unknowns,Nature Reviews Molecular Cell Biology,10(10):697-708
Surface L.E.,Thornton S.R.,and Boyer L.A.,2010,Polycomb group proteins set the stage for early lineage commitment,Cell Stem Cell,7(3):288-298
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.,and Brockdorff N.,2012,RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3,Cell,148(4):664-678
Zeng K.,and Liu M.,2017,Research progress of CBX protein and tumor,Shiyong Zhongliuxue Zazhi(Journal of Practical Oncology),31(2):165-169(曾凯,刘明,2017,CBX与肿瘤关系的研究进展,实用肿瘤学杂志,31(2):165-169)