Dataset Information

The m⁶A?methylase complex and mRNA export.

ABSTRACT: During synthesis, mRNA undergoes a number of modifications such as capping, splicing and polyadenylation. These processes are coupled with the orderly deposition of the TREX complex on the mRNA and subsequent recruitment of the NXF1-P15 heterodimer which stimulates the nuclear export of mature mRNAs. mRNAs also undergo a number of internal modifications, the most common of which is the N⁶?methyladenosine (m⁶A) modification. In this review we discuss the recent evidence of coupling between the m⁶A modification, RNA processing and export.

SUBMITTER: Lesbirel S

PROVIDER: S-EPMC6414750 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The m6A‑methylase complex and mRNA export.

Lesbirel Simon S Wilson Stuart A SA

Biochimica et biophysica acta. Gene regulatory mechanisms 20181002 3

During synthesis, mRNA undergoes a number of modifications such as capping, splicing and polyadenylation. These processes are coupled with the orderly deposition of the TREX complex on the mRNA and subsequent recruitment of the NXF1-P15 heterodimer which stimulates the nuclear export of mature mRNAs. mRNAs also undergo a number of internal modifications, the most common of which is the N6‑methyladenosine (m6A) modification. In this review we discuss the recent evidence of c ...[more]

PMID: 30290229

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Project description:BackgroundN6-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. The role of m6A mRNA methylation in the heart is not known.MethodsTo determine the role of m6A methylation in the heart, we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6A levels in cardiomyocytes by manipulating the levels of the m6A RNA methylase methyltransferase-like 3 (METTL3) both in culture and in vivo. We generated cardiac-restricted gain- and loss-of-function mouse models to allow assessment of the METTL3-m6A pathway in cardiac homeostasis and function.ResultsWe measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3 completely abrogated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, whereas increased expression of the m6A RNA methylase METTL3 was sufficient to promote cardiomyocyte hypertrophy both in vitro and in vivo. Finally, cardiac-specific METTL3 knockout mice exhibit morphological and functional signs of heart failure with aging and stress, showing the necessity of RNA methylation for the maintenance of cardiac homeostasis.ConclusionsOur study identified METTL3-mediated methylation of mRNA on N6-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes. Enhanced m6A RNA methylation results in compensated cardiac hypertrophy, whereas diminished m6A drives eccentric cardiomyocyte remodeling and dysfunction, highlighting the critical importance of this novel stress-response mechanism in the heart for maintaining normal cardiac function.

Dataset Information

The m⁶A?methylase complex and mRNA export.

Publications

The m<sup>6</sup>A‑methylase complex and mRNA export.

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OmicsDI is part of the ELIXIR infrastructure

Dataset Information

The m6A?methylase complex and mRNA export.

Publications

The m<sup>6</sup>A‑methylase complex and mRNA export.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

The m⁶A?methylase complex and mRNA export.