Abstract
The transcription factor HIF (hypoxia-inducible factor) mediates a highly pleiotrophic response to hypoxia. Many recent studies have focused on defining the extent of this transcriptional response. In the present study we have analysed regulation by hypoxia among transcripts encoding human Fe(II)- and 2-oxoglutarate-dependent oxygenases. Our results show that many of these genes are regulated by hypoxia and define two groups of histone demethylases as new classes of hypoxia-regulated genes. Patterns of induction were consistent across a range of cell lines with JMJD1A (where JMJD is Jumonji-domain containing) and JMJD2B demonstrating robust, and JMJD2C more modest, up-regulation by hypoxia. Functional genetic and chromatin immunoprecipitation studies demonstrated the importance of HIF-1alpha in mediating these responses. Given the importance of histone methylation status in defining patterns of gene expression under different physiological and pathophysiological conditions, these findings predict a role for the HIF system in epigenetic regulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acids, Dicarboxylic / metabolism
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Cell Line
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Deferoxamine / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Enzymologic*
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Humans
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Hypoxia*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Jumonji Domain-Containing Histone Demethylases
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Ketoglutaric Acids / metabolism
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Molecular Sequence Data
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Oligonucleotide Array Sequence Analysis
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism*
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Oxygenases / genetics
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Oxygenases / metabolism
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Promoter Regions, Genetic
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Protein Subunits / genetics
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Protein Subunits / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Siderophores / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Amino Acids, Dicarboxylic
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Hypoxia-Inducible Factor 1, alpha Subunit
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KDM4C protein, human
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Ketoglutaric Acids
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Neoplasm Proteins
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Protein Subunits
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RNA, Small Interfering
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Siderophores
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Transcription Factors
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Oxygenases
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Jumonji Domain-Containing Histone Demethylases
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KDM3A protein, human
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KDM4B protein, human
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Oxidoreductases, N-Demethylating
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Deferoxamine
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oxalylglycine