Molecular Therapy: Nucleic Acids (Dec 2021)
ALKBH5-mediated m6A mRNA methylation governs human embryonic stem cell cardiac commitment
- Zhenbo Han,
- Zihang Xu,
- Ying Yu,
- Yang Cao,
- Zhengyi Bao,
- Xinlu Gao,
- Danyu Ye,
- Gege Yan,
- Rui Gong,
- Juan Xu,
- Lai Zhang,
- Wenya Ma,
- Xiuxiu Wang,
- Fan Yang,
- Hong Lei,
- Ye Tian,
- Shijun Hu,
- Djibril Bamba,
- Ying Li,
- Desheng Li,
- Changzhu Li,
- Ning Wang,
- Ying Zhang,
- Zhenwei Pan,
- Baofeng Yang,
- Benzhi Cai
Affiliations
- Zhenbo Han
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Zihang Xu
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Ying Yu
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Yang Cao
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Zhengyi Bao
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Xinlu Gao
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Danyu Ye
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Gege Yan
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Rui Gong
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Juan Xu
- Department of Bioinformatics, Harbin Medical University, Harbin 150086, China
- Lai Zhang
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Wenya Ma
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Xiuxiu Wang
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Fan Yang
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Hong Lei
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Ye Tian
- Department of Cardiology at the First Affiliated Hospital, Harbin Medical University, Harbin 150086, China
- Shijun Hu
- Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou 215000, China
- Djibril Bamba
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Ying Li
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Desheng Li
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Changzhu Li
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Ning Wang
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Ying Zhang
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Zhenwei Pan
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China; Corresponding author: Zhenwei Pan, Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China.
- Baofeng Yang
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China; Corresponding author: Baofeng Yang, Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China.
- Benzhi Cai
- Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China; Institute of Clinical Pharmacy, the Heilongjiang Key Laboratory of Drug Research, Harbin Medical University, Harbin 150086, China; Corresponding author: Benzhi Cai, Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China.
- Journal volume & issue
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Vol. 26
pp. 22 – 33
Abstract
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.
