Author(s): Johnson AB, Denko N, Barton MC
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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.
This article was published in Mutat Res
and referenced in Pediatrics & Therapeutics