Cheng, Luo, Izzo, Pickering, Nguyen, Myers, Schurer, Gourkanti, Brüning, Vu, Jaffrey, Landau, Kharas (2019) m6A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment Cell reports 28(7) 1703-1716.e6

Abstract

Stem cells balance cellular fates through asymmetric and symmetric divisions in order to self-renew or to generate downstream progenitors. Symmetric commitment divisions in stem cells are required for rapid regeneration during tissue damage and stress. The control of symmetric commitment remains poorly defined. Using single-cell RNA sequencing (scRNA-seq) in combination with transcriptomic profiling of HSPCs (hematopoietic stem and progenitor cells) from control and m6A methyltransferase Mettl3 conditional knockout mice, we found that m6A-deficient hematopoietic stem cells (HSCs) fail to symmetrically differentiate. Dividing HSCs are expanded and are blocked in an intermediate state that molecularly and functionally resembles multipotent progenitors. Mechanistically, RNA methylation controls Myc mRNA abundance in differentiating HSCs. We identified MYC as a marker for HSC asymmetric and symmetric commitment. Overall, our results indicate that RNA methylation controls symmetric commitment and cell identity of HSCs and may provide a general mechanism for how stem cells regulate differentiation fate choice. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

干细胞通过不对称和对称分裂来平衡细胞命运,以便自我更新或产生下游祖细胞。干细胞中的对称承诺分裂是组织损伤和应激期间快速再生所必需的。对称承诺的控制仍然没有明确定义。使用单细胞RNA测序(scRNA-seq)与来自对照和m6A甲基转移酶Mettl3条件性敲除小鼠的HSPC(造血干细胞和祖细胞)的转录组学分析相结合,我们发现m6A缺陷的造血干细胞(HSC)不能对称区分。划分HSC被扩展并被阻断在分子和功能上类似于多能祖细胞的中间状态。机械地,RNA甲基化控制分化的HSC中的Myc mRNA丰度。我们将MYC确定为HSC不对称和对称承诺的标志。总之,我们的结果表明RNA甲基化控制HSC的对称性承诺和细胞特性,并且可以提供干细胞如何调节分化命运选择的一般机制。版权所有©2019作者。由Elsevier Inc.出版。保留所有权利。

Links

http://www.ncbi.nlm.nih.gov/pubmed/31412241
http://dx.doi.org/10.1016/j.celrep.2019.07.032

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