ALKBH5-mediated m6A mRNA methylation governs human embryonic stem cell cardiac commitment

• Published in: Molecular therapy. Nucleic acids Vol. 26; pp. 22 - 33
• Main Authors: Han, Zhenbo, Xu, Zihang, Yu, Ying, Cao, Yang, Bao, Zhengyi, Gao, Xinlu, Ye, Danyu, Yan, Gege, Gong, Rui, Xu, Juan, Zhang, Lai, Ma, Wenya, Wang, Xiuxiu, Yang, Fan, Lei, Hong, Tian, Ye, Hu, Shijun, Bamba, Djibril, Li, Ying, Li, Desheng, Li, Changzhu, Wang, Ning, Zhang, Ying, Pan, Zhenwei, Yang, Baofeng, Cai, Benzhi
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 03.12.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: Original
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2021.05.019

N6-methyladenosine (m6A), as the most abundant modification of mammalian messenger RNAs, is essential for tissue development and pathogenesis. However, the biological significance of m6A methylation in cardiac differentiation and development remains largely unknown. Here, we identify that the downregulation of m6A demethylase ALKBH5 is responsible for the increase of m6A methylation and cardiomyocyte fate determination of human embryonic stem cells (hESCs) from mesoderm cells (MESs). In contrast, ALKBH5 overexpression remarkably blocks cardiomyocyte differentiation of hESCs. Mechanistically, KDM5B and RBBP5, the components of H3K4 modifying enzyme complexes, are identified as downstream targets for ALKBH5 in cardiac-committed hESCs. Loss of function of ALKBH5 alters the expression of KDM5B and RBBP5 through impairing stability of their mRNAs, which in turn promotes the transcription of GATA4 by enhancing histone H3 Lys4 trimethylation (H3K4me3) at the promoter region of GATA4. Taken together, we reveal a previously unidentified role of m6A demethylase ALKBH5 in determining cardiac lineage commitment of hESCs. [Display omitted] Han et al. demonstrated that ALKBH5-mediated m6A modification regulates cardiomyocyte differentiation of human embryonic stem cells (hESCs) through affecting histone H3 Lys4 trimethylation (H3K4me3) at the promoter region of GATA4. This study provides new insights into the mechanisms by which RNA epigenetic modifications regulates cardiac lineage commitment.