Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis.

Abstract

Adaptation to hypoxia is mediated through a coordinated transcriptional response driven largely by hypoxia-inducible factor 1 (HIF-1). We used ChIP-chip and gene expression profiling to identify direct targets of HIF-1 transactivation on a genome-wide scale. Several hundred direct HIF-1 targets were identified and, as expected, were highly enriched for proteins that facilitate metabolic adaptation to hypoxia. Surprisingly, there was also striking enrichment for the family of 2-oxoglutarate dioxygenases, including the jumonji-domain histone demethylases. We demonstrate that these histone demethylases are direct HIF targets, and their up-regulation helps maintain epigenetic homeostasis under hypoxic conditions. These results suggest that the coordinated increase in expression of several oxygen-dependent enzymes by HIF may help compensate for decreased levels of oxygen under conditions of cellular hypoxia.

• Authors: Xiaobo Xia, Madeleine E Lemieux, Wei Li, Jason S Carroll, Myles Brown, X Shirley Liu, Andrew L Kung
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 11 Pg. 4260-5 (Mar 17 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19255431 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• Hypoxia-Inducible Factor 1
• Dioxygenases
• Oxidoreductases, N-Demethylating

Topics

• Adaptation, Physiological (genetics)
• Cell Line
• Dioxygenases (genetics)
• Gene Expression Profiling
• Genome, Human
• Histones (metabolism)
• Homeostasis
• Humans
• Hypoxia
• Hypoxia-Inducible Factor 1 (metabolism)
• Methylation
• Oxidoreductases, N-Demethylating (genetics)
• Transcriptional Activation