title: KDM6 demethylase independent loss of histone H3 lysine 27 trimethylation during early embryonic development.
abstract: The early mammalian embryo utilizes histone H3 lysine 27 trimethylation (H3K27me3) to maintain essential developmental genes in a repressive chromatin state. As differentiation progresses, H3K27me3 is removed in a distinct fashion to activate lineage specific patterns of developmental gene expression. These rapid changes in early embryonic chromatin environment are thought to be dependent on H3K27 demethylases. We have taken a mouse genetics approach to remove activity of both H3K27 demethylases of the Kdm6 gene family, Utx (Kdm6a, X-linked gene) and Jmjd3 (Kdm6b, autosomal gene). Male embryos null for active H3K27 demethylation by the Kdm6 gene family survive to term. At mid-gestation, embryos demonstrate proper patterning and activation of Hox genes. These male embryos retain the Y-chromosome UTX homolog, UTY, which cannot demethylate H3K27me3 due to mutations in catalytic site of the Jumonji-C domain. Embryonic stem (ES) cells lacking all enzymatic KDM6 demethylation exhibit a typical decrease in global H3K27me3 levels with differentiation. Retinoic acid differentiations of these ES cells demonstrate loss of H3K27me3 and gain of H3K4me3 to Hox promoters and other transcription factors, and induce expression similar to control cells. A small subset of genes exhibit decreased expression associated with reduction of promoter H3K4me3 and some low-level accumulation of H3K27me3. Finally, Utx and Jmjd3 mutant mouse embryonic fibroblasts (MEFs) demonstrate dramatic loss of H3K27me3 from promoters of several Hox genes and transcription factors. Our results indicate that early embryonic H3K27me3 repression can be alleviated in the absence of active demethylation by the Kdm6 gene family.
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Karl B
authors.initials: KB
authors.lastname: Shpargel
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Starmer
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Della
authors.initials: D
authors.lastname: Yee
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Pohlers
authors.affiliation: Department of Genetics, Carolina Center for Genome Sciences, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Terry
authors.initials: T
authors.lastname: Magnuson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D053595:Embryonic Stem Cells; D005260:Female; D018507:Gene Expression Regulation, Developmental; D056466:Histone Demethylases / Q000096:biosynthesis / Q000235:genetics*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D011247:Pregnancy
chemical_list: D002843:Chromatin; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C111778:Utx protein, mouse; C523761:Kdm6b protein, mouse
references.citation: Cell Rep. 2012 Nov 29;2(5):1244-58
references.pmid: 23103168
references.citation: J Biol Chem. 2012 Dec 28;287(53):44508-17
references.pmid: 23152497
references.citation: Cell. 2013 May 23;153(5):1149-63
references.pmid: 23664763
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):299-312
references.pmid: 18371364
references.citation: Hum Mol Genet. 2010 Jan 15;19(2):217-22
references.pmid: 19843542
references.citation: EMBO J. 2013 Apr 17;32(8):1075-86
references.pmid: 23503590
references.citation: Genes Dev. 1997 Apr 15;11(8):1061-72
references.pmid: 9136933
references.citation: Mol Cell Biol. 2001 Dec;21(23):8184-8
references.pmid: 11689706
references.citation: Development. 1991 Nov;113(3):913-7
references.pmid: 1821859
references.citation: Genes Dev. 2008 Jul 15;22(14):1865-70
references.pmid: 18628393
references.citation: Cell Stem Cell. 2009 Jan 9;4(1):80-93
references.pmid: 19128795
references.citation: J Biol Chem. 2014 Jun 27;289(26):18302-13
references.pmid: 24798337
references.citation: Dev Cell. 2012 Jan 17;22(1):25-37
references.pmid: 22192413
references.citation: Cell. 2012 Aug 31;150(5):922-33
references.pmid: 22921915
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15324-9
references.pmid: 22949634
references.citation: Nature. 2007 Oct 11;449(7163):731-4
references.pmid: 17713478
references.citation: Development. 1996 Oct;122(10):2977-86
references.pmid: 8898212
references.citation: Biochem Cell Biol. 2013 Apr;91(2):116-22
references.pmid: 23527641
references.citation: Genes Dev. 1998 Nov 15;12(22):3579-90
references.pmid: 9832509
references.citation: Cell. 2010 Apr 30;141(3):432-45
references.pmid: 20434984
references.citation: Dev Cell. 2011 Dec 13;21(6):993-1004
references.pmid: 22137762
references.citation: Cell Rep. 2013 Jun 27;3(6):1777-84
references.pmid: 23727241
references.citation: Cell Res. 2013 Jan;23(1):122-30
references.pmid: 22907667
references.citation: Nature. 2000 Mar 2;404(6773):95-9
references.pmid: 10716450
references.citation: Science. 2007 Oct 19;318(5849):447-50
references.pmid: 17761849
references.citation: Nature. 2007 Oct 11;449(7163):689-94
references.pmid: 17851529
references.citation: Development. 1995 Feb;121(2):273-85
references.pmid: 7768172
references.citation: Nature. 2007 Aug 2;448(7153):553-60
references.pmid: 17603471
references.citation: Cell Res. 2010 Feb;20(2):166-73
references.pmid: 20101266
references.citation: Nat Cell Biol. 2006 May;8(5):532-8
references.pmid: 16570078
references.citation: Development. 2013 Jul;140(14):2892-903
references.pmid: 23760957
references.citation: Nat Genet. 1998 Feb;18(2):136-41
references.pmid: 9462741
references.citation: Cell Stem Cell. 2010 Feb 5;6(2):153-66
references.pmid: 20144788
references.citation: Genes Dev. 1995 Sep 1;9(17):2105-16
references.pmid: 7657163
references.citation: PLoS One. 2013;8(4):e60020
references.pmid: 23573229
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10818-23
references.pmid: 17567753
references.citation: PLoS Genet. 2008 Oct;4(10):e1000242
references.pmid: 18974828
references.citation: Dev Biol. 2002 Apr 15;244(2):305-18
references.pmid: 11944939
references.citation: PLoS Genet. 2012;8(5):e1002647
references.pmid: 22570628
references.citation: Cell. 2007 Sep 21;130(6):1083-94
references.pmid: 17825402
references.citation: Cell. 2006 Apr 21;125(2):315-26
references.pmid: 16630819
references.citation: Genes Dev. 2009 May 15;23(10):1177-82
references.pmid: 19451218
references.citation: Science. 2010 May 28;328(5982):1161-4
references.pmid: 20508129
references.citation: Nature. 2012 Aug 16;488(7411):409-13
references.pmid: 22801502
references.citation: Nature. 2009 Jul 23;460(7254):473-8
references.pmid: 19525931
references.citation: PLoS One. 2010 Feb 10;5(2):e9150
references.pmid: 20161773
references.citation: Stem Cells. 2008 Jun;26(6):1496-505
references.pmid: 18403752
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18439-44
references.pmid: 18003914
references.citation: Cell. 2009 Apr 3;137(1):110-22
references.pmid: 19303136
references.citation: Nat Immunol. 2010 Oct;11(10):936-44
references.pmid: 20729857
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):286-98
references.pmid: 18371363
references.citation: Cell Res. 2010 Feb;20(2):154-65
references.pmid: 20084082
references.citation: Science. 2011 Oct 14;334(6053):194
references.pmid: 21940858
references.citation: Genes Dev. 2009 May 15;23(10):1171-6
references.pmid: 19451217
references.citation: Genome Res. 2010 Jun;20(6):722-32
references.pmid: 20395405
references.citation: Genesis. 2007 Jun;45(6):413-7
references.pmid: 17551945
references.citation: Genes Dev. 2010 Feb 15;24(4):327-32
references.pmid: 20123895
references.citation: Genes Dev. 2011 Nov 1;25(21):2266-77
references.pmid: 22002947
references.citation: Cell. 2013 May 23;153(5):1134-48
references.pmid: 23664764
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15782-7
references.pmid: 17043231
references.citation: PLoS One. 2008 Aug 21;3(8):e3034
references.pmid: 18716661
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10783-90
references.pmid: 20479220
references.citation: Cell. 2012 Nov 21;151(5):951-63
references.pmid: 23178118
references.citation: Development. 2010 Aug 1;137(15):2483-92
references.pmid: 20573702
references.citation: EMBO J. 2010 Apr 21;29(8):1401-11
references.pmid: 20300060
references.citation: Nat Cell Biol. 2008 Nov;10(11):1291-300
references.pmid: 18931660
references.citation: Nat Genet. 1999 Aug;22(4):361-5
references.pmid: 10431240
references.citation: Development. 2008 Feb;135(3):501-11
references.pmid: 18171685
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13004-9
references.pmid: 22826230
references.citation: Mol Cell. 2010 Nov 24;40(4):594-605
references.pmid: 21095589
references.citation: EMBO J. 2013 May 15;32(10):1393-408
references.pmid: 23584530
references.citation: PLoS Genet. 2012 Sep;8(9):e1002964
references.pmid: 23028370
references.citation: EMBO J. 2004 Oct 13;23(20):4061-71
references.pmid: 15385962
references.citation: Mol Cell Biol. 2001 Jul;21(13):4330-6
references.pmid: 11390661
references.citation: Development. 2013 Aug;140(16):3478-85
references.pmid: 23900545