title: Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase.
abstract: Histone H3 lysine 4 (H3K4) trimethylation (H3K4me3) at the promoter region of genes has been linked to transcriptional activation. In the present study, we found that hypoxia (1% oxygen) increased H3K4me3 in both normal human bronchial epithelial Beas-2B cells and human lung carcinoma A549 cells. The increase of H3K4me3 from hypoxia was likely caused by the inhibition of H3K4 demethylating activity, as hypoxia still increased H3K4me3 in methionine-deficient medium. Furthermore, an in vitro histone demethylation assay showed that 1% oxygen decreased the activity of H3K4 demethylases in Beas-2B nuclear extracts because ambient oxygen tensions were required for the demethylation reaction to proceed. Hypoxia only minimally increased H3K4me3 in the BEAS-2B cells with knockdown of JARID1A, which is the major histone H3K4 demethylase in this cell line. However, the mRNA and protein levels of JARID1A were not affected by hypoxia. GeneChip and pathway analysis in JARID1A knockdown Beas-2B cells revealed that JARID1A regulates the expression of hundreds of genes involved in different cellular functions, including tumorigenesis. Knocking down of JARID1A increased H3K4me3 at the promoters of HMOX1 and DAF genes. Thus, these results indicate that hypoxia might target JARID1A activity, which in turn increases H3K4me3 at both the global and gene-specific levels, leading to the altered programs of gene expression and tumor progression.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhou
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Haobin
authors.initials: H
authors.lastname: Chen
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Thomas
authors.initials: T
authors.lastname: Kluz
authors.forename: Adriana
authors.initials: A
authors.lastname: Arita
authors.forename: Max
authors.initials: M
authors.lastname: Costa
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001980:Bronchi / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D020869:Gene Expression Profiling; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008239:Lysine / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; C497442:HIF1A protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D008239:Lysine
references.citation: Carcinogenesis. 2008 Jan;29(1):2-8
references.pmid: 17916902
references.citation: Cell. 2007 Mar 23;128(6):1063-76
references.pmid: 17320161
references.citation: Biochem Med. 1973 Apr;7(2):241-52
references.pmid: 4704459
references.citation: Biochem J. 2008 Aug 15;414(1):19-29
references.pmid: 18651837
references.citation: J Biol Chem. 2004 Nov 5;279(45):46733-41
references.pmid: 15347669
references.citation: J Biol Chem. 2000 Mar 10;275(10):6922-7
references.pmid: 10702253
references.citation: Mol Carcinog. 2006 Jul;45(7):479-89
references.pmid: 16649251
references.citation: Nat Struct Mol Biol. 2008 Apr;15(4):419-21
references.pmid: 18270511
references.citation: Nature. 1991 Jul 18;352(6332):251-4
references.pmid: 1857421
references.citation: Nat Struct Mol Biol. 2007 Mar;14(3):240-2
references.pmid: 17310255
references.citation: Cell. 2007 Mar 23;128(6):1077-88
references.pmid: 17320160
references.citation: Mol Cell. 2005 Jun 10;18(6):623-35
references.pmid: 15949438
references.citation: BMC Genet. 2004 Sep 02;5:27
references.pmid: 15341671
references.citation: Curr Biol. 2004 Jul 27;14(14):R546-51
references.pmid: 15268870
references.citation: Biochim Biophys Acta. 2006 Aug;1766(1):42-52
references.pmid: 16784816
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30
references.pmid: 9380736
references.citation: FASEB J. 2005 Aug;19(10):1296-8
references.pmid: 15919761
references.citation: Cancer Metastasis Rev. 2008 Jun;27(2):253-61
references.pmid: 18330678
references.citation: Mol Cell. 2008 Aug 22;31(4):520-530
references.pmid: 18722178
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4260-5
references.pmid: 19255431
references.citation: Carcinogenesis. 2008 Sep;29(9):1831-6
references.pmid: 18321869
references.citation: Am J Hum Genet. 2005 Feb;76(2):227-36
references.pmid: 15586325
references.citation: Biochem Biophys Res Commun. 2008 Feb 8;366(2):563-7
references.pmid: 18078810
references.citation: Proc Natl Acad Sci U S A. 1968 Oct;61(2):748-55
references.pmid: 4386763
references.citation: Nature. 2007 Aug 2;448(7153):553-60
references.pmid: 17603471
references.citation: Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2607-10
references.pmid: 8146161
references.citation: Mutat Res. 2008 Apr 2;640(1-2):174-9
references.pmid: 18294659
references.citation: Mol Cell Biol. 2006 May;26(10):3728-37
references.pmid: 16648469
references.citation: Cell. 2007 Mar 9;128(5):889-900
references.pmid: 17320163
references.citation: Nat Genet. 2007 Mar;39(3):311-8
references.pmid: 17277777
references.citation: Genes Dev. 2008 May 15;22(10):1345-55
references.pmid: 18483221
references.citation: Cancer Res. 2006 Sep 15;66(18):9009-16
references.pmid: 16982742
references.citation: Int J Cancer. 2002 Oct 20;101(6):581-8
references.pmid: 12237901
references.citation: Nature. 2000 Jan 6;403(6765):41-5
references.pmid: 10638745
references.citation: Nat Rev Mol Cell Biol. 2005 Nov;6(11):838-49
references.pmid: 16261189
references.citation: J Clin Invest. 1999 Apr;103(7):1047-54
references.pmid: 10194478