title: Additional sex combs-like 2 is required for polycomb repressive complex 2 binding at select targets.
abstract: Polycomb Group (PcG) proteins are epigenetic repressors of gene expression. The Drosophila Additional sex combs (Asx) gene and its mammalian homologs exhibit PcG function in genetic assays; however, the mechanism by which Asx family proteins mediate gene repression is not well understood. ASXL2, one of three mammalian homologs for Asx, is highly expressed in the mammalian heart and is required for the maintenance of cardiac function. We have previously shown that Asxl2 deficiency results in a reduction in the bulk level of histone H3 lysine 27 trimethylation (H3K27me3), a repressive mark generated by the Polycomb Repressive Complex 2 (PRC2). Here we identify several ASXL2 target genes in the heart and investigate the mechanism by which ASXL2 facilitates their repression. We show that the Asxl2-deficient heart is defective in converting H3K27me2 to H3K27me3 and in removing ubiquitin from mono-ubiquitinated histone H2A. ASXL2 and PRC2 interact in the adult heart and co-localize to target promoters. ASXL2 is required for the binding of PRC2 and for the enrichment of H3K27me3 at target promoters. These results add a new perspective to our understanding of the mechanisms that regulate PcG activity and gene repression.
authors.affiliation: Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Hsiao-Lei
authors.initials: HL
authors.lastname: Lai
authors.forename: Q Tian
authors.initials: QT
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D056426:Genetic Loci; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits; D021381:Protein Transport; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C484296:ASXL2 protein, mouse; C575444:BAP1 protein, mouse; D002843:Chromatin; D006657:Histones; D021122:Protein Subunits; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C021645:chromatin conjugate protein A24; D063151:Polycomb Repressive Complex 2; D043222:Ubiquitin Thiolesterase
references.citation: Science. 2002 Nov 1;298(5595):1039-43
references.pmid: 12351676
references.citation: Mol Gen Genet. 1999 Jun;261(4-5):753-61
references.pmid: 10394912
references.citation: Development. 2009 Nov;136(21):3531-42
references.pmid: 19820181
references.citation: J Biol Chem. 2010 Jan 1;285(1):18-29
references.pmid: 19880879
references.citation: Nature. 2006 Jul 6;442(7098):91-5
references.pmid: 16728978
references.citation: J Biol Chem. 2001 Nov 16;276(46):43065-73
references.pmid: 11571280
references.citation: Development. 2003 Jan;130(2):285-94
references.pmid: 12466196
references.citation: Development. 2006 Dec;133(24):4957-68
references.pmid: 17107999
references.citation: Mol Cell. 1998 Jun;1(7):1057-64
references.pmid: 9651589
references.citation: EMBO J. 2003 Mar 17;22(6):1347-58
references.pmid: 12628927
references.citation: Int J Oncol. 2004 Jun;24(6):1617-22
references.pmid: 15138607
references.citation: Cell Cycle. 2008 May 1;7(9):1173-7
references.pmid: 18418041
references.citation: Neuromuscul Disord. 2009 Jan;19(1):6-16
references.pmid: 18976909
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):299-312
references.pmid: 18371364
references.citation: Nat Cell Biol. 2009 Jan;11(1):46-55
references.pmid: 19079247
references.citation: Mol Cell Biol. 2008 Mar;28(5):1862-72
references.pmid: 18086877
references.citation: Ann Thorac Surg. 2001 Apr;71(4):1320-4
references.pmid: 11308180
references.citation: Nature. 2008 Aug 7;454(7205):766-70
references.pmid: 18600261
references.citation: Genes Dev. 2006 May 1;20(9):1123-36
references.pmid: 16618801
references.citation: Nature. 2007 Aug 2;448(7153):553-60
references.pmid: 17603471
references.citation: Gene. 2003 Mar 13;306:115-26
references.pmid: 12657473
references.citation: Front Biosci (Landmark Ed). 2011 Jun 01;16:3047-60
references.pmid: 21622221
references.citation: Development. 1998 Apr;125(7):1207-16
references.pmid: 9477319
references.citation: J Biol Chem. 2006 Jun 30;281(26):17588-98
references.pmid: 16606617
references.citation: Genes Dev. 2002 Nov 15;16(22):2893-905
references.pmid: 12435631
references.citation: PLoS Genet. 2008 Oct;4(10):e1000242
references.pmid: 18974828
references.citation: Curr Biol. 2005 May 24;15(10):942-7
references.pmid: 15916951
references.citation: PLoS Biol. 2009 Jan 13;7(1):e13
references.pmid: 19143474
references.citation: Annu Rev Genet. 1995;29:289-303
references.pmid: 8825476
references.citation: Mol Cell Biol. 2010 Nov;30(21):5071-85
references.pmid: 20805357
references.citation: J Mol Cell Cardiol. 2012 Nov;53(5):734-41
references.pmid: 23046516
references.citation: Mol Cell. 2004 Jul 2;15(1):57-67
references.pmid: 15225548
references.citation: Gene. 2006 Mar 15;369:109-18
references.pmid: 16412590
references.citation: Mol Cell Biol. 2002 Nov;22(21):7473-83
references.pmid: 12370294
references.citation: Nature. 2009 Oct 8;461(7265):762-7
references.pmid: 19767730
references.citation: Cell Cycle. 2012 Jan 1;11(1):119-31
references.pmid: 22186017
references.citation: Cancer Cell. 2012 Aug 14;22(2):180-93
references.pmid: 22897849
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):286-98
references.pmid: 18371363
references.citation: Mol Cell Biol. 2000 Nov;20(22):8602-12
references.pmid: 11046155
references.citation: Development. 2008 Aug;135(14):2383-90
references.pmid: 18550707
references.citation: Int J Oncol. 2003 Sep;23(3):845-50
references.pmid: 12888926
references.citation: EMBO J. 2007 Sep 19;26(18):4078-88
references.pmid: 17762866
references.citation: Trends Biochem Sci. 2006 Jan;31(1):35-40
references.pmid: 16297627
references.citation: Curr Opin Genet Dev. 1997 Aug;7(4):488-94
references.pmid: 9309179
references.citation: PLoS One. 2009;4(3):e4750
references.pmid: 19270745
references.citation: PLoS One. 2009 Dec 01;4(12):e8106
references.pmid: 19956620
references.citation: Dev Biol. 2010 Jan 1;337(1):9-15
references.pmid: 19833123
references.citation: Nature. 2008 Jul 3;454(7200):49-55
references.pmid: 18509334
references.citation: Cell Stem Cell. 2010 Sep 3;7(3):288-98
references.pmid: 20804966
references.citation: Mol Gen Genet. 1995 Feb 6;246(3):291-300
references.pmid: 7854314
references.citation: Nature. 2010 May 13;465(7295):243-7
references.pmid: 20436459
references.citation: Mol Cell Biol. 2008 Apr;28(8):2718-31
references.pmid: 18285464
references.citation: EMBO J. 2004 Oct 13;23(20):4061-71
references.pmid: 15385962
references.citation: Nature. 2006 Jul 6;442(7098):86-90
references.pmid: 16728976
references.citation: Mol Cell Biol. 2006 Apr;26(7):2560-9
references.pmid: 16537902
references.citation: Nat Genet. 2012 Jan 22;44(3):343-7
references.pmid: 22267199