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

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.

SUBMITTER: Han Z

PROVIDER: S-EPMC8408434 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Han Zhenbo Z Xu Zihang Z Yu Ying Y Cao Yang Y Bao Zhengyi Z Gao Xinlu X Ye Danyu D Yan Gege G Gong Rui R Xu Juan J Zhang Lai L Ma Wenya W Wang Xiuxiu X Yang Fan F Lei Hong H Tian Ye Y Hu Shijun S Bamba Djibril D Li Ying Y Li Desheng D Li Changzhu C Wang Ning N Zhang Ying Y Pan Zhenwei Z Yang Baofeng B Cai Benzhi B

Molecular therapy. Nucleic acids 20210529

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 (hE ...[more]

PMID: 34513291

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Project description:BackgroundRadiation-induced hepatic stellate cell (HSC) activation promotes radiation-induced liver fibrosis (RILF), a complication for hepatocellular carcinoma (HCC) radiotherapy. The demethylase alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) decreases N6-methyladenylate methylation (m6 A) modification of RNA, while its role in regulating RILF pathogenesis and HCC radiosensitivity remains unknown.MethodsMethylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-sequencing (RNA-seq) were used to screen target genes regulated by ALKBH5. HSC with altered ALKBH5 expression was used to assess irradiation-induced HSC activation and the effect of HSC on recruitment and polarisation of monocytes. Key cytokines in medium from irradiated HSC-educated monocytes were identified by cytokine array detection. The effects of blocking ALKBH5 and key cytokines on RILF and HCC radiosensitivity were also evaluated.ResultsRadiation-induced ALKBH5 expression in HSC mediated m6 A demethylation of toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) mRNA and activated its downstream NF-κB and JNK/Smad2 pathways to promote HSC activation. Additionally, ALKBH5 regulated CCL5 secretion by irradiated HSC to promote monocyte recruitment and M2 macrophage polarisation. Notably, polarised monocytes secreted CCL20 to up-regulate ALKBH5 expression in HSC, and reduce HCC radiosensitivity by activating ALKBH5/TIRAP axis in HCC cells. ALKBH5 knockdown-combined CCR6 (CCL20 receptor) inhibitor significantly alleviated RILF and improved HCC radiosensitivity in mice. HCC patients with high ALKBH5 and TIRAP expression were prone to radiation-induced liver injury and poor tumour response to radiotherapy.ConclusionsCollectively, irradiation up-regulates ALKBH5 in HSC to mediate monocyte recruitment and M2 polarisation and form positive feedback to promote RILF and reduce HCC radiosensitivity. The dual roles of ALKBH5 as a microenvironmental regulator and radiosensitisation target provide new ideas for RILF prevention and radiosensitisation of HCC.

Dataset Information

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

Publications

ALKBH5-mediated m<sup>6</sup>A mRNA methylation governs human embryonic stem cell cardiac commitment.

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