Abstract
PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.
Highlights
The cellular response to decreased oxygen tension is characterised by changes in the gene expression program primarily mediated by the hypoxia-inducible factor (HIF) family of transcription factors
We found that PBRM1 is required for full HIF activity and HIF-1α protein levels
This regulation occurs through promoting efficient translation of HIF-1α mRNA rather than through direct effects on HIF-1α gene transcription. This activity is supported by PBRM1’s ability to bind selectively to HIF-1α mRNA as well as the RNA-binding protein YTHDF2, which is required for normal levels of HIF-1α protein in specific cellular backgrounds
Summary
The cellular response to decreased oxygen tension (hypoxia) is characterised by changes in the gene expression program primarily mediated by the hypoxia-inducible factor (HIF) family of transcription factors. PHD enzymes are inhibited, leading to the stabilisation and accumulation of HIF-α isoforms. This results in active transcription of HIF target genes [2]. In order to facilitate the extensive changes in gene expression necessary for the cellular response to hypoxic stress, changes to the chromatin structure must take place for transcription factors such as HIF to access the promoter regions of its target genes. One mechanism of regulating chromatin structure is through the action of ATP-dependent remodelling complexes, which can result in either increased or decreased gene transcription [3]. There are four families of ATP-dependent remodelling complexes, imitation switch (ISWI), chromodomain helicase
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