The Histone Demethylases JMJD1A and JMJD2B Are Transcriptional Targets of Hypoxia-inducible Factor HIF

Posttranslational histone modifications serve to store epigenetic information and control both nucleosome assembly and recruitment of non-histone proteins. Histone methylation occurs on arginine and lysine residues and is involved in the regulation of gene transcription. A dynamic control of these modifications is exerted by histone methyltransferases and the recently discovered histone demethylases. Here we show that the hypoxia-inducible factor HIF-1α binds to specific recognition sites in the genes encoding the jumonji family histone demethylases JMJD1A and JMJD2B and induces their expression. Accordingly, hypoxic cells express elevated levels of JMJD1A and JMJD2B mRNA and protein. Furthermore, we find increased expression of JMJD1A and JMJD2B in renal cancer cells that have lost the von Hippel Lindau tumor suppressor protein VHL and therefore display a deregulated expression of hypoxia-inducible factor. Studies on ectopically expressed JMJD1A and JMJD2B indicate that both proteins retain their histone lysine demethylase activity in hypoxia and thereby might impact the hypoxic gene expression program. Posttranslational histone modifications serve to store epigenetic information and control both nucleosome assembly and recruitment of non-histone proteins. Histone methylation occurs on arginine and lysine residues and is involved in the regulation of gene transcription. A dynamic control of these modifications is exerted by histone methyltransferases and the recently discovered histone demethylases. Here we show that the hypoxia-inducible factor HIF-1α binds to specific recognition sites in the genes encoding the jumonji family histone demethylases JMJD1A and JMJD2B and induces their expression. Accordingly, hypoxic cells express elevated levels of JMJD1A and JMJD2B mRNA and protein. Furthermore, we find increased expression of JMJD1A and JMJD2B in renal cancer cells that have lost the von Hippel Lindau tumor suppressor protein VHL and therefore display a deregulated expression of hypoxia-inducible factor. Studies on ectopically expressed JMJD1A and JMJD2B indicate that both proteins retain their histone lysine demethylase activity in hypoxia and thereby might impact the hypoxic gene expression program. Methylation of histones contributes to dynamic changes in chromatin structure (1Bannister A.J. Zegerman P. Partridge J.F. Miska E.A. Thomas J.O. Allshire R.C. Kouzarides T. Nature. 2001; 410: 120-124Crossref PubMed Scopus (2139) Google Scholar, 2Kim J. Daniel J. Espejo A. Lake A. Krishna M. Xia L. Zhang Y. Bedford M.T. EMBO Rep. 2006; 7: 397-403Crossref PubMed Scopus (384) Google Scholar, 3Lachner M. O'Carroll D. Rea S. Mechtler K. Jenuwein T. Nature. 2001; 410: 116-120Crossref PubMed Scopus (2145) Google Scholar, 4Taverna S.D. Ilin S. Rogers R.S. Tanny J.C. 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In general, di- and trimethylation of histone H3K4, H3K36, and H3K79 appear as hallmarks of active regions of chromatin, whereas the same modifications on H3K9, H3K27, and H4K20 are enriched in condensed, heterochromatic regions. However, it has proven difficult to classify histone marks as simply activating or repressing (6Berger S.L. Nature. 2007; 447: 407-412Crossref PubMed Scopus (2095) Google Scholar). Recently, several members of the Jumonji protein family, which is characterized by the catalytic Jumonji C (JmjC) 2The abbreviations used are: JmjCjumonji C domainJMJD1Ajumonji domain containing 1AJMJD2Bjumonji domain containing 2BJMJD2C/GASC1jumonji domain containing 2C/gene amplified in squamous cell carcinoma 1ChIPchromatin immunoprecipitationFIHfactor inhibiting HIFHIFhypoxia-inducible factorHREHIF-responsive elementDFOdesferrioxamineH3K9histone H3 lysine 9H3K27histone H3 lysine 27H3K9me3trimethylated histone H3 lysine 9H3K9me2dimethylated histone H3 lysine 9Oct4octamer-binding protein 4RCCrenal clear cell carcinoma18S18 S ribosomal RNAsiRNAsmall interfering RNAVEGFvascular endothelial growth factorVHLvon Hippel Lindau tumor suppressorFACSfluorescence-activated cell sortingHAhemagglutininHEKhuman embryonic kidney 2The abbreviations used are: JmjCjumonji C domainJMJD1Ajumonji domain containing 1AJMJD2Bjumonji domain containing 2BJMJD2C/GASC1jumonji domain containing 2C/gene amplified in squamous cell carcinoma 1ChIPchromatin immunoprecipitationFIHfactor inhibiting HIFHIFhypoxia-inducible factorHREHIF-responsive elementDFOdesferrioxamineH3K9histone H3 lysine 9H3K27histone H3 lysine 27H3K9me3trimethylated histone H3 lysine 9H3K9me2dimethylated histone H3 lysine 9Oct4octamer-binding protein 4RCCrenal clear cell carcinoma18S18 S ribosomal RNAsiRNAsmall interfering RNAVEGFvascular endothelial growth factorVHLvon Hippel Lindau tumor suppressorFACSfluorescence-activated cell sortingHAhemagglutininHEKhuman embryonic kidney domain, have been identified as histone demethylases (reviewed in Refs. 8Klose R.J. 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Y. Y. M. 2006; PubMed Scopus Google we a in di- or trimethylation levels in hypoxic In of JMJD1A or JMJD2B or of both proteins on histone methylation levels C and are the of JMJD1A in in a on methylation Y. G. Y. Zhang Y. Nature. 2007; PubMed Scopus Google Scholar). it has been that and of impact levels of (10Cloos P.A. Christensen J. Agger K. Maiolica A. Rappsilber J. Antal T. Hansen K.H. Helin K. Nature. 2006; 442: 307-311Crossref PubMed Scopus (599) Google Scholar, 11Klose R.J. Yamane K. Bae Y. Zhang D. Erdjument-Bromage H. Tempst P. Wong J. Zhang Y. Nature. 2006; 442: 312-316Crossref PubMed Scopus (514) Google Scholar). However, of in a in H3 methylation the target gene R.J. Yamane K. Bae Y. Zhang D. Erdjument-Bromage H. Tempst P. Wong J. Zhang Y. Nature. 2006; 442: 312-316Crossref PubMed Scopus (514) Google whereas cell proliferation (10Cloos P.A. Christensen J. Agger K. Maiolica A. Rappsilber J. Antal T. Hansen K.H. Helin K. 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