m6A metabolism in cardiomyozytes

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Similar to DNA modifications, an epitranscriptome of mRNA modifications emerged over the last few years in the cardiovascular system. Specifically, the discovery of the N6-methyladenosine (m6A) as reversible posttranscriptional modification in mRNAs raised scientific interest in those modifications in cardiomyocytes and their role in diseased hearts. mRNA modifications have been recognized as a relevant mechanism for the regulation of gene expression in diseased cardiomyocytes. Consequently, m6A-mRNA-methylomes of human cardiac tissue and of animal model heart-samples were reported and shed point towards an important role of m6A modifications on cardiac function and in the pathophysiology of heart failure. The presence of m6A across different species, the conservation of writers, erasers and readers and the severe phenotypes associated with depletion of involved regulatory proteins suggest a fundamental role of m6A in cardiac physiology and pathophysiology. However, how changes in methylation of specific transcripts in response to stress are regulated in cardiomyocytes and which reader proteins are involved in post-transcriptional control of gene expression by m6A is largely unknown. We identified in a high-throughput screen that the expression as well as activity of adenosyltransferase 2 alpha (Mat2a) is increased in cardiomyocytes after acute pressure overload induced by transverse aortic constriction (TAC). Mat2a generates S-adenosylmethionine (SAM) using methionine and Adenosine triphosphate (ATP). SAM is the primary donor of methyl groups to different transmethylation reactions and is also used for RNA methylation via RNA methyltransferases. Moreover, the expression of the m6A reader protein "YTH domain-containing family protein 2" (Ythdf2) is increased failing myocardium. The function of Mat2a as well as Ythdf2 in the heart is largely unknown. We aim to study mechanisms responsible for m6A methylation and characterize the impact of key proteins regulating m6A-metabolism on cardiac function in vitro and in vivo using state of the art methods.