Stage-specific requirement for Mettl3-dependent m6A mRNA methylation during haematopoietic stem cell differentiation
Stage-specific requirement for Mettl3-dependent m6A mRNA methylation during haematopoietic stem cell differentiation
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DOI：
10.1038/s41556-019-0318-1
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发表时间：
2019-06-01
影响因子：
21.3
通讯作者：
Ding, Lei
中科院分区：
文献类型：
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作者：
Lee, Heather;Bao, Suying;Ding, Lei
造血干细胞(HSCs)维持平衡的自我更新和分化，但这些功能是如何被精确调控的还不完全清楚。N-6-甲基腺苷(m(6)A)信使RNA甲基化已成为影响多种生物学过程的一种重要的表位基因表达调控方式。我们发现，从成人造血系统中删除m(6)A甲基转移酶METTL3会导致造血干细胞在骨髓中积聚，并由于阻止造血干细胞分化而显著降低重建潜力。有趣的是，使用Lysm-cre从髓系细胞中删除METTL3并不影响髓系细胞的数量或功能。RNA测序显示，在HSC中有2,073个基因具有显著的m(6)A修饰。MYC是造血干细胞中m(6)A的直接靶点。METTL3基因缺陷的HSCs在刺激分化后不能上调MYC的表达，增强Myc的表达挽救了METTL3基因缺陷HSCs的分化缺陷。我们的结果揭示了m(6)A在调节HSC分化中的关键作用。
Haematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation, but how these functions are precisely regulated is not fully understood. N-6-methyladenosine (m(6)A) messenger RNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deletion of the m(6)A methyltransferase Mettl3 from the adult haematopoietic system led to an accumulation of HSCs in the bone marrow and a marked reduction of reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not impact myeloid cell number or function. RNA sequencing revealed 2,073 genes with significant m(6)A modifications in HSCs. Myc was identified as a direct target of m(6)A in HSCs. Mettl3-deficient HSCs failed to upregulate MYC expression following stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results reveal a key role of m(6)A in governing HSC differentiation.