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-Despite its functional importance in various fundamental bioprocesses, the studies of N6-methyladenosine (m6A) in the heart are lacking. Here we show that, fat mass and obesity-associated (FTO), an m6A demethylase, plays a critical role in cardiac contractile function during homeostasis, remodeling and regeneration. -We used clinical human samples, preclinical pig and mouse models and primary cardiomyocyte cell cultures to study the functional role of m6A and FTO in the heart and in cardiomyocytes. We modulated expression of FTO using AAV9 (in vivo), adenovirus (both in vivo and in vitro) and siRNAs (in vitro) to study its function in regulating cardiomyocyte m6A, calcium dynamics and contractility and cardiac function post-ischemia. We performed methylated (m6A) RNA immunoprecipitation sequencing (MeRIP-seq) to map transcriptome-wide m6A, and MeRIP qPCR assays to map and validate m6A in individual transcripts, in healthy and failing hearts and myocytes. -We discovered that FTO has decreased expression in failing mammalian hearts and hypoxic cardiomyocytes, thereby increasing m6A in RNA and decreasing cardiomyocyte contractile function. Improving expression of FTO in failing mouse hearts attenuated the ischemia-induced increase in m6A and decrease in cardiac contractile function. This is carried out by the demethylation activity of FTO, which selectively demethylates cardiac contractile transcripts, thus preventing their degradation and improving their protein expression under ischemia. Additionally, we demonstrate that FTO overexpression in mouse models of MI decreased fibrosis and enhanced angiogenesis. -Collectively, our study demonstrates the functional importance of FTO-dependent cardiac m6A methylome in cardiac contraction during heart failure and provides a novel mechanistic insight into the therapeutic mechanisms of FTO.

New isotope data obtained from relatively conformable, carbonate-rich strata of the Ediacaran Yangtze platform in South China reveal substantial δ 13 C variability. In platform sections, four negative δ 13 C anomalies with a nadir down to ≤− 8‰ (PDB) are present in the interval between the cap carbonate level (∼ 635 Ma) and the Precambrian/Cambrian boundary (∼ 542 Ma), while in slope and basinal sections, δ 13 C values are negative through the entire Doushantuo Formation (∼635-551 Ma). If these δ 13 C values are close to their primary seawater signature, they imply a strong (≥ 10‰) surface-to-deep ocean δ 13 C gradient that is consistent with long-term deep ocean anoxia and the presence of a large dissolved organic carbon (DOC) reservoir. The two prominent negative δ 13 C excursions within the Doushantuo Formation above the cap carbonate level are associated with shoaling and local exposure of the platform. The anomalies may thus record remineralization of a large oceanic DOC pool via sulfate reduction that transferred 13 C-depleted carbon from the oceanic DOC reservoir to the surface ocean during regression. Inconsistencies in Ediacaran δ 13 C profiles globally and variations in South China in particular highlight the need for further evaluation of local departures in δ 13 C from an inferred average seawater signature.

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