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Hypoxia‐induced recruitment of HDAC1 to the VEGF promoter of pulmonary artery endothelial cells (PAECs)
Author(s) -
Middleton N. S.,
Gorodnya O.,
Ruchko M.,
Gillespie M. N.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a924
Subject(s) - trichostatin a , chromatin , chromatin remodeling , histone deacetylase , histone , microbiology and biotechnology , hypoxia (environmental) , chemistry , gene expression , nucleosome , regulation of gene expression , biology , gene , biochemistry , organic chemistry , oxygen
The family of histone deacetylases (HDACs) includes 11 members that play central roles in gene expression by regulating chromatin remodeling. Which of the 11 HDACs contributes to hypoxia‐induced gene expression is unknown. To address this issue in the context of hypoxia‐induced VEGF expression, we used DNA affinity precipitation analyses to identify HDACs present in PAEC nuclear extract that associated with an oligonucleotide probe corresponding to the VEGF hypoxic response element (HRE). We found that HDACs 1,2,6,7, and 9 associated constitutively with VEGF HRE, with the abundance of HDAC‐1, but not the other HDACs, increasing in the hypoxia‐inducible transcriptional complex. Increases in HDAC‐1 binding were accompanied by elevations in probe‐associated HDAC activity. Using a nuclease digestion assay, we found that the non‐selective HDAC inhibitor, trichostatin A (TSA), caused chromatin aggregation into nuclease‐resistant structures and prevented the hypoxia‐induced redistribution of the VEGF HRE to transcriptionally active mono‐ and di‐nucleosome fractions. TSA also blocked hypoxia‐induced VEGF mRNA expression. These findings indicate that HDAC activity, probably associated with HDAC1, is required for chromatin remodeling at the VEGF promoter and VEGF mRNA expression. Supported by NIH