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

Abstract

N6-methyladenosine (m 6 A), as the most abundant modification of mammalian messenger RNAs, is essential for tissue development and pathogenesis. However, the biological significance of m 6 A methylation in cardiac differentiation and development remains largely unknown. Here, we identify that the downregulation of m 6 A demethylase ALKBH5 is responsible for the increase of m 6 A 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 m 6 A demethylase ALKBH5 in determining cardiac lineage commitment of hESCs.

Ethionine-mediated reduction of S-adenosylmethionine is responsible for the neural tube defects in the developing mouse embryo-mediated m6A modification and is involved in neural tube defects via modulating Wnt/β-catenin signaling pathway

“…The generation, proliferation, differentiation, and migration of neural cells and the resulting morphological changes are the cytological basis of neural tube development, and any abnormalities in this process can cause neural tube defects [ 30 , 31 ]. Recent studies have revealed that m6A methylation is linked to embryonic development [ 32 , 33 ]. Moreover, m6A modification plays an important role in facilitating early development via regulation of SAM availability [ 34 ].…”

“…Increasing evidences indicate that m6A modification plays an important role in mammals, and that the METTL3 mutation is lethal to both mammalian and plant embryos [ 34 ]. Recent research found that ALKBH5-mediated m6A RNA modification plays a critical role in cardiac differentiation [ 32 ]. However, the role of m6A RNA modification in neural tube development remains unknown.…”

The Role of m6A on Female Reproduction and Fertility: From Gonad Development to Ovarian Aging

“…For example, m 6 A played a decisive role on cell fate during the endothelial-to-haematopoietic transition to specify the earliest haematopoietic stem/progenitor cells during zebrafish embryogenesis, which was blocked in METTL3 deficient embryos ( Zhang et al, 2017 ). The downregulation of ALKBH5 was responsible for the cardiomyocyte fate determination of human embryonic stem cells (hESCs) originated from mesoderm cells ( Han et al, 2021 ). Currently, m 6 A modification in neuromuscular system development has been clarified in many studies.…”

N6-Methyladenosine RNA Modification: A Potential Regulator of Stem Cell Proliferation and Differentiation

“…The fusion of the catalytic domain of ALKBH5 with a stably transfected, doxycycline-inducible dCas13a precisely and reversibly demethylated the targeted m 6 A site of Sox2 , which significantly increased the amount and stability of corresponding transcripts and facilitated the differentiation of hESCs without affecting the self-renewal capacity ( Chen X. et al, 2021 ). In addition, overexpression of ALKBH5 remarkably blocked cardiomyocyte differentiation of hESCs by down-regulating the expression of KDM5B and RBBP5, two downstream targets for ALKBH5 in cardiac-committed hESCs ( Han et al, 2021 ).…”

“…3) Although the m 6 A demethylase FTO and ALKBH5 are reported to facilitate leukemogenesis, their effects on proliferation and differentiation of HSCs have not been investigated. However, FTO and ALKBH5 demethylate m 6 A RNA to promote the mRNA stability and affect nuclei-to-cytoplasm transport of targets to regulate the proliferation and differentiation of stem cells such as ESCs and BMSCs ( Chen X. et al, 2021 ; Li Z. et al, 2021 ; Han et al, 2021 ). More researches are in requirement to elucidate the role of FTO and ALKBH5 in the cell fate determination of HSCs, thus facilitating their application in treating diseases such as AML.…”