title: 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.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Xia
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Lemieux
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
mesh_terms: 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
chemical_list: D006657:Histones; D051793:Hypoxia-Inducible Factor 1; D049308:Dioxygenases; D010089:Oxidoreductases, N-Demethylating