BRG1 and BRM Chromatin-Remodeling Complexes Regulate the Hypoxia Response by Acting as Coactivators for a Subset of Hypoxia-Inducible Transcription Factor Target Genes

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 1␣ (HIF1␣) and HIF2␣ 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.H ypoxia (Hx) is a common characteristic of many solid tumors. The Hx intratumoral microenvironment stabilizes hypoxia-inducible transcription factor 1␣ (HIF1␣) and HIF2␣, which are normally degraded under normoxia (Nx). The stabilized HIF1␣ and HIF2␣ proteins translocate to the nucleus, where they dimerize with the constitutive nuclear protein ARNT (the aryl hydrocarbon receptor nuclear translocator, also called HIF1␤) to form HIF1␣/ARNT (HIF1) and HIF2␣/ARNT (HIF2) heterodimers. HIF1 and HIF2 bind to HIF binding sites (HBS) on HIF target gene promoters and/or enhancers and transactivate genes involved in neovascularization, glycolysis, cellular proliferation, and metastasis. Thus, the HIF-mediated Hx transcriptional response is critical for tumor progression by allowing cancer cells to adapt to a low-oxygen environment (1-4). However, recent reports indicate that the HIF2-and particularly the HIF1-mediated Hx response can activate tumor-suppressive genes, such as Scgb3a, Bnip3, Bnip3L, Nix, MYC inhibitor Mxi, p21, and p27, in a cell-type-specific manner (5-10).It is well established that multiple transcription factors (TFs) are required to achieve maximal activation of target genes in response to a specific stimulus such as Hx. This multifactorial transcription complex has been termed the "enhanceosome." Individual TFs in the enhanceosome complex may promote transcription by recruiting RNA polymerase II/general TFs and/or by recruiting chromatin-modifying enzymes such as histone acetylase, CBP and p300, and the chromatin-remodeling SWI/SNF complex. In the context of the enhanceosome associated with the Hx response, two additional TFs, STAT3 and USF2, are required for maximal Hx response (11,12). STAT3 and USF2 function...

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

“…7F). Chromatin remodeling factors, such as BRG1, BRM, and SWI/ SNF, are implicated in HIF-mediated transcriptional activation (64,65). Therefore, these factors may be recruited to the Epo gene locus by HIF2␣, which binds to EpoHE in hypoxic cells.…”

Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis

“…Both Brg1 and Brm are also known to interact with and stimulate the activity of several transcription factors, including the glucocorticoid receptor and C/EBP [16,17]. Other studies have suggested a functional redundancy between Brm and Brg1 [18][19][20][21].…”

“…Brg1 binds to zinc finger protein through a unique N-terminal domain not present in Brm, while Brm interacts with two ankyrin-repeats proteins that are crucial in the Notch signal transduction [30]. More recently, studies have investigated the individual roles of Brg1 and Brm in various cellular processes, revealing again individual, cooperating, and redundant activities of these two proteins depending on the cell type and the specific context [18][19][20][21].…”

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

“…Although little is known about the role of chromatin remodelers in ischemia-induced chromatin condensation, several ATP-dependent chromatin remodelers have been shown to regulate HIF transcriptional activity. The key components of the SWI/SNF complex, BRG1 and BRM, promote expression of a subset of HIF target genes in human cancer cell lines in an ATPase-dependent manner [98]. Upon hypoxia, BRG1 is recruited by HIF to the hypoxia response elements of CA9 and EPO and induces nucleosome remodeling at these gene promoters [98, 99].…”

“…The key components of the SWI/SNF complex, BRG1 and BRM, promote expression of a subset of HIF target genes in human cancer cell lines in an ATPase-dependent manner [98]. Upon hypoxia, BRG1 is recruited by HIF to the hypoxia response elements of CA9 and EPO and induces nucleosome remodeling at these gene promoters [98, 99]. BRG1 and BRM also enhance the recruitment of RNA polymerase II to the EPO gene in hypoxic Hep3B cells [100].…”