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Trimethylated histone H3 lysine 27 (H3K27me3) is linked to gene silencing, whereas H3K4me3 is associated with gene activation. These two marks frequently co-occupy gene promoters, forming bivalent domains. Bivalency signifies repressed but activatable states of gene expression and can be resolved to active, H3K4me3-prevalent states during multiple cellular processes, including differentiation, development and epithelial mesenchymal transition. However, the molecular mechanism underlying bivalency resolution remains largely unknown. Here, we show that the H3K27 demethylase UTX (also called KDM6A) is required for the resolution and activation of numerous retinoic acid (RA)-inducible bivalent genes during the RA-driven differentiation of mouse embryonic stem cells (ESCs). Notably, UTX loss in mouse ESCs inhibited the RA-driven bivalency resolution and activation of most developmentally critical homeobox (Hox) a-d genes. The UTX-mediated resolution and activation of many bivalent Hox genes during mouse ESC differentiation were recapitulated during RA-driven differentiation of human NT2/D1 embryonal carcinoma cells. In support of the importance of UTX in bivalency resolution, Utx-null mouse ESCs and UTX-depleted NT2/D1 cells displayed defects in RA-driven cellular differentiation. Our results define UTX as a bivalency-resolving histone modifier necessary for stem cell differentiation.

Titel:	An essential role for UTX in resolution and activation of bivalent promoters.
Autor/in / Beteiligte Person:	Dhar, SS ; Lee, SH ; Chen, K ; Zhu, G ; Oh, W ; Allton, K ; Gafni, O ; Kim, YZ ; Tomoiga, AS ; Barton, MC ; Hanna, JH ; Wang, Z ; Li, W ; Lee, MG
Zeitschrift:	Nucleic acids research, Jg. 44 (2016-05-05), Heft 8, S. 3659-74
Veröffentlichung:	1992- : Oxford : Oxford University Press ; <i>Original Publication</i>: London, Information Retrieval ltd., 2016
Medientyp:	academicJournal
ISSN:	1362-4962 (electronic)
DOI:	10.1093/nar/gkv1516
Schlagwort:	Animals Cell Differentiation drug effects Cell Line, Tumor Cells, Cultured Embryonic Stem Cells cytology Embryonic Stem Cells drug effects Embryonic Stem Cells metabolism Genes, Homeobox Histone Demethylases metabolism Humans Mice Nuclear Proteins metabolism Tretinoin pharmacology Cell Differentiation genetics Histone Demethylases physiology Nuclear Proteins physiology Promoter Regions, Genetic Transcriptional Activation
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Nucleic Acids Res] 2016 May 05; Vol. 44 (8), pp. 3659-74. <i>Date of Electronic Publication: </i>2016 Jan 13. MeSH Terms: Promoter Regions, Genetic* ; Transcriptional Activation* ; Cell Differentiation / genetics ; Histone Demethylases / physiology ; Nuclear Proteins / *physiology ; Animals ; Cell Differentiation / drug effects ; Cell Line, Tumor ; Cells, Cultured ; Embryonic Stem Cells / cytology ; Embryonic Stem Cells / drug effects ; Embryonic Stem Cells / metabolism ; Genes, Homeobox ; Histone Demethylases / metabolism ; Humans ; Mice ; Nuclear Proteins / metabolism ; Tretinoin / pharmacology References: Nat Genet. 2008 Jul;40(7):897-903. (PMID: 18552846) ; Structure. 2015 Oct 6;23(10):1921-33. (PMID: 26320581) ; PLoS One. 2008;3(8):e3034. (PMID: 18716661) ; Cell Stem Cell. 2009 Jan 9;4(1):80-93. (PMID: 19128795) ; Dev Biol. 2009 Apr 15;328(2):456-71. (PMID: 19217899) ; Genome Biol. 2009;10(3):R25. (PMID: 19261174) ; Cell. 2009 Sep 4;138(5):1019-31. (PMID: 19698979) ; EMBO J. 2010 Apr 21;29(8):1401-11. (PMID: 20300060) ; Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10783-90. (PMID: 20479220) ; Cell Metab. 2011 Aug 3;14(2):161-72. (PMID: 21803287) ; Dev Cell. 2012 Jan 17;22(1):25-37. (PMID: 22192413) ; Cell. 2012 Apr 27;149(3):590-604. (PMID: 22541430) ; Bioinformatics. 2012 Jul 1;28(13):1805-6. (PMID: 22543366) ; Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13004-9. (PMID: 22826230) ; Nature. 2012 Aug 16;488(7411):409-13. (PMID: 22801502) ; Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15324-9. (PMID: 22949634) ; Cell. 2012 Sep 28;151(1):181-93. (PMID: 23021224) ; PLoS Genet. 2012 Sep;8(9):e1002964. (PMID: 23028370) ; Genes Dev. 2012 Dec 15;26(24):2749-62. (PMID: 23249737) ; Hum Mutat. 2013 Jan;34(1):108-10. (PMID: 23076834) ; Genome Res. 2013 Feb;23(2):341-51. (PMID: 23193179) ; Science. 2013 Mar 29;339(6127):1567-70. (PMID: 23539597) ; PLoS One. 2013;8(4):e60020. (PMID: 23573229) ; Genes Dev. 2013 Jun 15;27(12):1318-38. (PMID: 23788621) ; Am J Med Genet A. 2013 Sep;161A(9):2234-43. (PMID: 23913813) ; Nat Struct Mol Biol. 2013 Sep;20(9):1093-7. (PMID: 23934151) ; Development. 2013 Oct;140(19):3951-63. (PMID: 24046316) ; Cell Growth Differ. 2002 Jun;13(6):257-64. (PMID: 12114215) ; Cell. 2002 Aug 9;110(3):385-97. (PMID: 12176325) ; Genome Biol. 2003;4(5):P3. (PMID: 12734009) ; Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7135-40. (PMID: 12782789) ; Nature. 1990 Aug 23;346(6286):763-6. (PMID: 1975088) ; Dev Biol. 1995 Apr;168(2):342-57. (PMID: 7729574) ; Biochem J. 2005 May 15;388(Pt 1):363-9. (PMID: 15628969) ; Nat Rev Genet. 2005 Dec;6(12):893-904. (PMID: 16341070) ; Cell. 2006 Apr 21;125(2):315-26. (PMID: 16630819) ; Mol Cell Biol. 2007 Mar;27(5):1889-903. (PMID: 17178841) ; J Biol Chem. 2007 Jul 13;282(28):20395-406. (PMID: 17500065) ; Mol Cell Biol. 2013 Dec;33(23):4745-54. (PMID: 24081332) ; Nature. 2007 Aug 2;448(7153):553-60. (PMID: 17603471) ; Cell. 2007 Sep 21;130(6):1083-94. (PMID: 17825402) ; Nature. 2007 Oct 11;449(7163):731-4. (PMID: 17713478) ; Nature. 2007 Oct 11;449(7163):689-94. (PMID: 17851529) ; Cell Res. 2007 Oct;17(10):850-7. (PMID: 17923864) ; Science. 2007 Oct 19;318(5849):447-50. (PMID: 17761849) ; Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18439-44. (PMID: 18003914) ; Anal Chem. 2008 Mar 1;80(5):1702-8. (PMID: 18251521) ; Cell Stem Cell. 2007 Sep 13;1(3):286-98. (PMID: 18371363) ; Cell Stem Cell. 2007 Sep 13;1(3):299-312. (PMID: 18371364) ; Stem Cells. 2008 Apr;26(4):886-93. (PMID: 18238853) ; Mol Cell. 2008 Jun 20;30(6):755-66. (PMID: 18514006) ; J Clin Invest. 2013 Dec;123(12):5231-46. (PMID: 24200691) ; Elife. 2013;2:e01503. (PMID: 24368734) ; Nucleic Acids Res. 2014 Jan;42(1):205-23. (PMID: 24078252) ; Nat Rev Genet. 2014 Feb;15(2):93-106. (PMID: 24366184) ; Development. 2014 Feb;141(3):526-37. (PMID: 24423662) ; Cancer Res. 2014 Mar 15;74(6):1705-17. (PMID: 24491801) ; J Biol Chem. 2014 Jun 27;289(26):18302-13. (PMID: 24798337) ; Stem Cells. 2014 Jun;32(6):1451-8. (PMID: 25099890) ; PLoS Genet. 2014 Aug;10(8):e1004507. (PMID: 25101834) ; Genome Biol. 2013;14(12):R144. (PMID: 24367927) ; Nucleic Acids Res. 2015 Apr 20;43(7):e47. (PMID: 25605792) ; Nature. 2008 Jul 3;454(7200):49-55. (PMID: 18509334) Grant Information: R01 CA157919 United States CA NCI NIH HHS; R01 ES025761 United States ES NIEHS NIH HHS; R01 GM095659 United States GM NIGMS NIH HHS; R01 HG007538 United States HG NHGRI NIH HHS Substance Nomenclature: 0 (Nuclear Proteins) ; 5688UTC01R (Tretinoin) ; EC 1.14.11.- (Histone Demethylases) ; EC 1.14.11.- (KDM6A protein, human) ; EC 1.14.11.- (Utx protein, mouse) Entry Date(s): Date Created: 20160115 Date Completed: 20170605 Latest Revision: 20210109 Update Code: 20231215 PubMed Central ID: PMC4856969

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An essential role for UTX in resolution and activation of bivalent promoters.