Hypoxia induces a novel signature of chromatin modifications and global repression of transcription.
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.
Johnson
Amber Buescher
AB
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.
Denko
Nicholas
N
Barton
Michelle Craig
MC
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
D006657:Histones; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D012313:RNA