Shi Weili, Chen Rui, Zhou Mingjie, Li Yunian, Zhang Yuwei, Wang Jikui, Hao Bingtao, Liao Shixiu
Henan Provincial People's Hospital, Medical Genetics Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, People's Hospital of Zhengzhou University, Zhengzhou, China.
National Health Commission Key Laboratory of Birth Defect Prevention, Henan Key Laboratory of Population Defects Prevention, Zhengzhou, China.
Cell Death Discov. 2024 Sep 6;10(1):396. doi: 10.1038/s41420-024-02164-3.
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.
唐氏综合征（DS）由额外的21号染色体所致，患先天性心脏病（CHD）的风险很高，这是DS新生儿死亡的主要原因之一。为了阐明这种情况背后的致病机制，我们探讨了由METTL3调控的RNA m6A甲基化在DS心脏发育中的作用及其对位于唐氏综合征先天性心脏病（DS-CHD）最小区域的SH3BGR基因表达的影响。我们分析了DS胎儿心脏组织，以评估RNA m6A甲基化水平并确定潜在的影响因素。进行RNA测序以检测同一组织中差异表达的基因。为了进一步了解METTL3在心脏发育中的功能，我们在发育中的小鼠心脏中使Mettl3失活，以模拟在DS心脏发育中观察到的METTL3显著降低的情况。此外，使用人类心肌细胞AC16细胞来研究METTL3调节SH3BGR表达的分子机制。通过分析细胞凋亡来评估METTL3通过SH3BGR调控对心脏发育的影响。在人类DS胎儿心脏中观察到m6A修饰减少和METTL3表达降低，同时SH3BGR表达显著增加。发现METTL3通过m6A修饰，通过影响mRNA稳定性来调节SH3BGR表达。METTL3缺陷的小鼠胚胎表现出心脏畸形且细胞凋亡增加，强调了其在心脏发育中的作用。在DS心脏中，METTL3下调和SH3BGR上调，可能由异常的m6A修饰所协调，导致基因失调和细胞凋亡。这项研究揭示了对DS心脏病理学的新见解，突出了METTL3在DS先天性心脏病中的复杂作用，并将SH3BGR的m6A修饰作为一个潜在的治疗靶点。
