detection-of-global-dna-methylation-in-the-hearts-of-zebrafish-larvae

Detection of Global DNA Methylation in the Hearts of Zebrafish Larvae

DNA methylation is one of the most extensively studied epigenetic modifications and&#160;plays an essential role in cardiac development. The zebrafish is ...

Suzhou Medical College of Soochow University

An ever-increasing body of research has established a link between maternal PM2.5 exposure and congenital heart diseases in the offspring, but the underlying mechanisms remain elusive. We recently reported that activation of the aryl hydrocarbon receptor (AHR) by PM2.5 causes aberrant mA RNA methylation, leading to cardiac malformations in zebrafish embryos. We hypothesized that PM2.5 can disrupt heart development by inducing mA methylation changes through AHR in mammals. In this study, we observed that extractable organic matters (EOM) from PM significantly impaired cardiomyocyte differentiation in embryonic rat cardiomyoblasts H9c2. Importantly, EOM exposure reduced global mA methylation levels, which was reversed by AHR inhibition. Moreover, AHR, activated by EOM directly promoted the transcription of the demethylase, FTO, leading to global mA hypomethylation. Specifically, AHR-induced FTO overexpression decreased the mA methylation levels of Nox4 mRNA, resulting in NOX4 overexpression and subsequent oxidative stress in EOM samples. We then demonstrated that oxidative stress contributes to the inhibition of cardiomyocyte differentiation by EOM through suppression of Wnt/β-catenin signaling. In summary, our findings indicate that AHR activation by PM directly enhances the expression of the demethylase, FTO, which increases NOX4 expression by reducing its mA methylation. The oxidative stress caused by NOX4 overexpression inhibits Wnt/β-catenin signaling, thereby compromising cardiomyocyte differentiation.

Shoushuang Zhao

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