Abstract
Chromatin remodeling is an active process, which represses or enables the access of transcription machinery to genes in response to external stimuli, including hypoxia. However, in hypoxia, the specific requirement, as well as the molecular mechanism by which the chromatin-remodeling complexes regulate gene expression, remains unclear. In this study, we report that the Brahma (BRM) and Brahma-related gene 1 (BRG1) ATPase-containing SWI/SNF chromatin-remodeling complexes promote the expression of the hypoxia-inducible transcription factor 1α (HIF1α) and HIF2α genes and also promote hypoxic induction of a subset of HIF1 and HIF2 target genes. We show that BRG1 or BRM knockdown in Hep3B and RCC4T cells reduces hypoxic induction of HIF target genes, while reexpression of BRG1 or BRM in BRG1/BRM-deficient SW13 cells increases HIF target gene activation. Mechanistically, HIF1 and HIF2 increase the hypoxic induction of HIF target genes by recruiting BRG1 complexes to HIF target gene promoters, which promotes nucleosome remodeling of HIF target gene promoters in a BRG1 ATPase-dependent manner. Importantly, we found that the function of BRG1 complexes in hypoxic SW13 and RCC4T cells is dictated by the HIF-mediated hypoxia response and could be opposite from their function in normoxic SW13 and RCC4T cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiopoietin-Like Protein 4
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Angiopoietins / genetics
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Angiopoietins / metabolism
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Blotting, Western
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Carbonic Anhydrase IX
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Carbonic Anhydrases / genetics
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Carbonic Anhydrases / metabolism
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Cell Hypoxia
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Cell Line, Tumor
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Cell Movement
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Cell Proliferation
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Chromatin Assembly and Disassembly*
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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Erythropoietin / genetics
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Erythropoietin / metabolism
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Gene Expression
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HEK293 Cells
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Humans
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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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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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RNA Interference
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Receptor-Like Protein Tyrosine Phosphatases, Class 3 / genetics
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Receptor-Like Protein Tyrosine Phosphatases, Class 3 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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ANGPTL4 protein, human
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Angiopoietin-Like Protein 4
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Angiopoietins
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Antigens, Neoplasm
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Basic Helix-Loop-Helix Transcription Factors
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EPO protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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SMARCA2 protein, human
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Transcription Factors
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Erythropoietin
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endothelial PAS domain-containing protein 1
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PTPRB protein, human
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Receptor-Like Protein Tyrosine Phosphatases, Class 3
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SMARCA4 protein, human
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DNA Helicases
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CA9 protein, human
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Carbonic Anhydrase IX
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Carbonic Anhydrases