The m6A methyltransferase METTL3 promotes hypoxic pulmonary arterial hypertension

Qin, Yuhan; Ye, Qiao; Li, Linqing; Luo, Erfei; Wang, Dong; Yao, Yuyu; Tang, Chengchun; Yan, Gaoliang

doi:10.1016/j.lfs.2021.119366

Cited by 58 publications

(63 citation statements)

References 48 publications

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“…Furthermore, studies of liver cancer have shown that hypoxia can increase the levels of m6A in mRNA [45]. More recently, METTL3, one of the m6A writers, has been shown to promote hypoxia-induced hypertension in pulmonary arteries [46]. Our data demonstrating that HIF-1α is m6Amodified adds to the hypothesis that, indeed, the epitranscriptome is an integral part of the cellular response to hypoxia.…”

Section: Discussionsupporting

confidence: 58%

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: Discussionsupporting

confidence: 58%

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

Shmakova

Frost

Batie

et al. 2021

Cells

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show abstract

“…Furthermore, studies in liver cancer have shown that hypoxia can increase the levels of m6A in mRNA [44]. More recently, METTL3, one of the m6A writers, was shown to promote hypoxia induced hypertension in pulmonary arteries [45]. Our data demonstrating that HIF-1 is m6A modified adds to the hypothesis that indeed the epitranscriptome is an integral part of the cellular response to hypoxia.…”

Section: Discussionsupporting

confidence: 59%

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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“…Recent study confirmed that elevated m 6 A methylation and increased expression of YTHDF1 exist in pulmonary arterial hypertension, furthermore, YTHDF1 promotes pulmonary artery smooth muscle cells proliferation and PAH via enhancing MAGED1 translation [ 44 ]. However, there are only sporadic study concerned expression and function of methylation modifying enzymes in PAH [ 44 , 45 ]. In this study, expression of methylation modifying enzyme in lung tissues of PAH rats was detected, results showed decreased expressions of FTO and ALKBH5 accompanied with increased expressions of METTL3 and YTHDF1, while there was no significant difference in expressions of other methylation modifying enzyme between PAH and control rats.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension

Zeng

Huang

Zuo

et al. 2021

Aging

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Background: N6-methyladenosine (m 6 A) modification is one of the most common chemical modifications of eukaryotic mRNAs, which play an important role in tumors and cardiovascular disease through regulating mRNA stability, splicing and translation. However, the changes of m 6 A mRNA and m 6 A-related enzymes in pulmonary arterial hypertension (PAH) remain largely unexplored. Methods: MeRIP-seq was used to identify m 6 A methylation in lung tissues from control and MCT-PAH rats. Western blot and immunofluorescence were used to evaluate expression of m 6 A-related enzymes. Results: Compared with control group, m 6 A methylation was mainly increased in lung tissues from MCT-PAH rats. The up-methylated coding genes in MCT-PAH rats were primarily enriched in processes associated with inflammation, glycolysis, ECM-receptor interaction and PDGF signal pathway, while genes with down-methylation were enriched in processes associated with TGF-β family receptor members. The expression of FTO and ALKBH5 downregulated, METTL3 and YTHDF1 increased and other methylation modification-related proteins was not significantly changed in MCT-PAH rats lung tissues. Immunofluorescence indicated that expression of FTO decreased and YTHDF1 increased in small pulmonary arteries of MCT-PAH rats. Conclusion: m 6 A levels and the expression of methylation-related enzymes were altered in PAH rats, in which FTO and YTHDF1 may play a crucial role in m 6 A modification.

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The m6A methyltransferase METTL3 promotes hypoxic pulmonary arterial hypertension

Cited by 58 publications

References 48 publications

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

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

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

Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension

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