Journal
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume 640, Issue 1-2, Pages 174-179Publisher
ELSEVIER
DOI: 10.1016/j.mrfmmm.2008.01.001
Keywords
hypoxic stress; chromatin; HIF-1; transcription; repression
Funding
- NCI NIH HHS [T32 CA009299, T32-CA009299, CA100132, R01 CA100132] Funding Source: Medline
- NIGMS NIH HHS [R01 GM053683-10, GM053686, R01 GM053683] Funding Source: Medline
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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. (C) 2008 Elsevier B.V. All rights reserved.
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