TY - JOUR
T1 - Hypoxia induces a novel signature of chromatin modifications and global repression of transcription
AU - Johnson, Amber Buescher
AU - Denko, Nicholas
AU - Barton, Michelle Craig
N1 - Funding Information:
We apologize to our colleagues whose work we failed to cite, due to space limitations. We are especially grateful to P. Corn and M. Czyzyk-Krzeska for use of their hypoxic incubators in times of need. This work was supported in part by grant GM053686 to M.C.B. and grant CA100132 to N.D. from the National Institutes of Health. A.B.J. is a trainee supported by grant T32-CA009299 from the National Institutes of Health.
PY - 2008/4/2
Y1 - 2008/4/2
N2 - 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.
AB - 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.
KW - Chromatin
KW - HIF-1
KW - Hypoxic stress
KW - Repression
KW - Transcription
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U2 - 10.1016/j.mrfmmm.2008.01.001
DO - 10.1016/j.mrfmmm.2008.01.001
M3 - Article
C2 - 18294659
AN - SCOPUS:40649114443
SN - 0027-5107
VL - 640
SP - 174
EP - 179
JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
IS - 1-2
ER -