title: Hypoxia induces a novel signature of chromatin modifications and global repression of transcription.
abstract: Tumor cells respond to the harsh hypoxic microenvironment, in part, by transcriptional regulation of specific target genes. We found that hypoxia-mediated activation of selected genes occurs amidst widespread repression of transcription that is neither cell type-specific nor HIF-1-dependent. Despite overall repression, hypoxia induces a pool of histone modifications typically associated with transcriptional activation or repression. Chromatin immunoprecipitation analyses showed that this global mixture of hypoxia-modified histones is sorted in a gene-specific manner to correlate with transcriptional response to hypoxia. Exceptions to this were unexpected increases in H3K4me3 levels, typically associated with transcriptional activation, and decreased H3K27me3 levels, generally a marker of transcriptional silencing, at core promoters of both hypoxia-activated and -repressed genes. These data suggest that a novel signature of chromatin modifications is induced under hypoxic stress, which may play a role in gene regulatory switches active in proliferating tumor cells undergoing cycles of hypoxia and reoxygenation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biomedical Sciences, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Amber Buescher
authors.initials: AB
authors.lastname: Johnson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Denko
authors.forename: Michelle Craig
authors.initials: MC
authors.lastname: Barton
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051379:Mice; D012313:RNA / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D012313:RNA