Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis.
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.
Xia
Xiaobo
X
Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.
Lemieux
Madeleine E
ME
Li
Wei
W
Carroll
Jason S
JS
Brown
Myles
M
Liu
X Shirley
XS
Kung
Andrew L
AL
D000222:Adaptation, Physiological / Q000235:genetics; D002460:Cell Line; D049308:Dioxygenases / Q000235:genetics; D020869:Gene Expression Profiling; D015894:Genome, Human; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D015533:Transcriptional Activation
D006657:Histones; D051793:Hypoxia-Inducible Factor 1; D049308:Dioxygenases; D010089:Oxidoreductases, N-Demethylating