小柯机器人

YTHDC1调控细胞命运机制
2021-03-07 21:29

中国科学院广州生物医学与健康研究所陈捷凯研究组近日取得一项新成果。他们发现RNA N6-甲基腺苷(m6A)阅读器YT521-B同源域含蛋白1(YTHDC1)使逆转座子沉默并保卫胚胎干(ES)细胞身份。2021年3月3日出版的《自然》杂志发表了这项成果。

他们显示了m6A阅读器YTHDC1是维持m6A依赖方式的小鼠ES细胞所必需的,并且其缺失会引发细胞重编程为2C样的状态。从机制上讲,YTHDC1与小鼠ES细胞中反转录转座子的转录物(如脑池内A颗粒,ERVK和LINE1)结合,其耗竭导致这些沉默的反转录转座子重新激活,并伴随着SETDB1介导的组蛋白H3的9位赖氨酸三甲基化(H3K9me3)的整体降低。

他们进一步证明,YTHDC1及其靶标m6A RNA在SETDB1的上游起作用,以抑制逆转座子和Dux(两细胞阶段(2C)样程序的主要诱导物)。这项研究揭示了m6A RNA和YTHDC1在染色质修饰和反转录转座子阻遏中的重要作用。

据悉,RNA修饰m6A在许多生物学过程中均具有关键作用。然而,m6A在哺乳动物发育早期的功能仍然知之甚少。

附:英文原文

Title: The RNA m 6 A reader YTHDC1 silences retrotransposons and guards ES cell identity

Author: Jiadong Liu, Mingwei Gao, Jiangping He, Kaixin Wu, Siyuan Lin, Lingmei Jin, Yaping Chen, He Liu, Junjie Shi, Xiwei Wang, Lei Chang, Yingying Lin, Yu-Li Zhao, Xiaofei Zhang, Man Zhang, Guan-Zheng Luo, Guangming Wu, Duanqing Pei, Jie Wang, Xichen Bao, Jiekai Chen

Issue&Volume: 2021-03-03

Abstract: The RNA modification N6-methyladenosine (m6A) has critical roles in many biological processes1,2. However, the function of m6A in the early phase of mammalian development remains poorly understood. Here we show that the m6A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m6A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m6A RNA and YTHDC1 in chromatin modification and retrotransposon repression. N6-methyladenosine RNA and its reader YTHDC1 serve as a bridge to silencing retrotransposons through the RNA derived from these retrotransposons in mouse ES cells.

DOI: 10.1038/s41586-021-03313-9

Source: https://www.nature.com/articles/s41586-021-03313-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0