Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

Frost, Julianty; Frost, Mark; Batie, Michael; Jiang, Hao; Rocha, Sónia

doi:10.3390/cancers13020350

Cited by 27 publications

(19 citation statements)

References 325 publications

(113 reference statements)

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“…The m6A eraser proteins, FTO and ALKBH5, are 2-oxoglutarate dioxygenases, meaning they use 2-oxoglutarate, iron and oxygen as cofactors. Although their oxygen affinity might be too high to participate in the hypoxia response [43], ALKBH5 has been shown to be a target of HIF-1α [44]. This suggests that, indeed, hypoxia can influence the epitranscriptome in a cell.…”

Section: Discussionmentioning

confidence: 99%

PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

Shmakova

Frost

Batie

et al. 2021

Cells

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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.

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Section: Discussionmentioning

confidence: 99%

PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

Shmakova

Frost

Batie

et al. 2021

Cells

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“…Whilst the central oxygen-sensing pathway in metazoans is the VHL-PHD-HIF axis, impairment of other oxygen sensitive enzymes in low oxygen, and non-HIF targets PHD enzymes, can trigger other oxygen sensitive changes (14). This includes changes to DNA and histone methylation (28). In an attempt to delineate HIF stabilisation in hypoxia, from other effects caused by inhibition of cellular oxygen sensors, we performed ATAC-seq in cells treated with a chemical stabiliser of HIF-α, called VH298.…”

Section: Discussionmentioning

confidence: 99%

“…Histone methylation modifications are sensitive to hypoxia (28) and KDM5A is reported cellular oxygen sensor that regulates H3K4me3 in hypoxia (12). We show that hypoxia induced upregulation of H3K4me3 is enriched at hypoxia upregulated accessibility sites.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Chromatin Accessibility by hypoxia and HIF

Batie

Frost

Shakir

et al. 2022

Preprint

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Reduced oxygen availability (hypoxia) can act as a signalling cue in physiological processes such as development, but also in pathological conditions such as cancer or ischaemic disease. As such, understanding how cells and organisms respond to hypoxia is of great importance. The family of transcription factors called Hypoxia Inducible Factors (HIFs) coordinate a transcriptional programme required for survival and adaptation to hypoxia. The effects of hypoxia and HIF on the chromatin accessibility landscape are still unclear. Here, using genome wide mapping of chromatin accessibility via ATAC-seq, we find hypoxia induces loci specific changes in chromatin accessibility enriched at hypoxia transcriptionally responsive genes. These changes are predominantly HIF dependent, reversible upon reoxygenation and partially mimicked by chemical HIF stabilisation independent of molecular dioxygenase inhibition. This work demonstrates that indeed, HIF stabilisation is necessary and sufficient to alter chromatin accessibility in hypoxia, with implications for our understanding of gene expression regulation by hypoxia and HIF.

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“…The m6A eraser proteins, FTO and ALKBH5 are 2-oxoglutarate dioxygenases, meaning they use 2-oxoglutarate, iron and oxygen as cofactors. Although, their oxygen affinity might be too high to participate in the hypoxia response [42], ALKBH5 has been shown to be a target of HIF-1 [43]. This suggests that indeed hypoxia can influence the epitranscriptome in a cell.…”

Section: Discussionmentioning

confidence: 99%

PBRM1 Cooperates with YTHDF2 to Control HIF-1Alpha Protein Translation

Shmakova¹,

Frost²,

Kenneth³

et al. 2021

Preprint

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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-1alpha activity. We find that PBRM1 is required for HIF-1alpha transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1alpha mRNA translation, as absence of PBRM1 results in reduced activly transalting HIF-1alpha mRNA. Interestingly, we find that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1alpha mRNA is m6A modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1alpha mRNA and reduction of YTHDF2 results in reduced HIF-1alpha protein expression in cells. Our results identify a SWI/SNF independent function for PBRM1, interacting with HIF-1alpha mRNA and the epitranscriptome machinery. Furthermore, our results suggests that the epitranscriptome associated proteins play a role in the control of hypoxia signalling pathways

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Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

Cited by 27 publications

References 325 publications

PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

Regulation of Chromatin Accessibility by hypoxia and HIF

PBRM1 Cooperates with YTHDF2 to Control HIF-1Alpha Protein Translation

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