Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase.
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.
Zhou
Xue
X
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
Sun
Hong
H
Chen
Haobin
H
Zavadil
Jiri
J
Kluz
Thomas
T
Arita
Adriana
A
Costa
Max
M
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
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
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