Methyltransferase METTL3 governs the modulation of SH3BGR expression through m6A methylation modification, imparting influence on apoptosis in the context of Down syndrome-associated cardiac development

Abstract Down syndrome (DS), caused by an additional chromosome 21, has a high risk of congenital heart defects (CHD), one of the primary causes of mortality in DS newborns. To elucidate the pathogenetic mechanisms underlying this condition, we explored the role of RNA m6A methylation, regulated by METTL3, in DS cardiac development and its impact on the expression of SH3BGR, a gene located at Down syndrome congenital heart disease (DS-CHD) minimal region. We analyzed DS fetal cardiac tissues to assess RNA m6A methylation levels and identify potential contributors. RNA sequencing was performed to detect differentially expressed genes in the same tissues. To further understand METTL3’s function in heart development, we inactivated Mettl3 in the developing mouse heart to mimic the significantly reduced METTL3 observed in DS cardiac development. Additionally, human cardiomyocyte AC16 cells were used to investigate the molecular mechanism by which METTL3 regulates SH3BGR expression. Apoptosis was analyzed to evaluate METTL3’s effect on heart development through SH3BGR regulation. Reduced m6A modification and decreased METTL3 expression were observed in human DS fetal hearts, along with a significant increase of SH3BGR expression. METTL3, through m6A modification, was found to regulate SH3BGR expression, by influencing mRNA stability. METTL3-deficient mouse embryos exhibited heart malformation with increased apoptosis, emphasizing its role in heart development. In DS hearts, METTL3 downregulation and SH3BGR upregulation, potentially orchestrated by abnormal m6A modification, contribute to gene dysregulation and apoptosis. This study reveals novel insights into DS cardiac pathology, highlighting the intricate role of METTL3 in DS congenital heart defects and presenting the m6A modification of SH3BGR as a potential therapeutic target.