| Literature DB >> 33505026 |
Wenqi Xu1,2,3, Jiahui Li1,2, Chenxi He1,2, Jing Wen1,2, Honghui Ma1,2, Bowen Rong1,2, Jianbo Diao1,2, Liyong Wang1,2, Jiahua Wang1,2, Feizhen Wu1,2, Li Tan1,2, Yujiang Geno Shi4, Yang Shi5, Hongjie Shen6,7.
Abstract
METTL3 (methyltransferase-like 3) mediates the N6-methyladenosine (m6A) methylation of mRNA, which affects the stability of mRNA and its translation into protein1. METTL3 also binds chromatin2-4, but the role of METTL3 and m6A methylation in chromatin is not fully understood. Here we show that METTL3 regulates mouse embryonic stem-cell heterochromatin, the integrity of which is critical for silencing retroviral elements and for mammalian development5. METTL3 predominantly localizes to the intracisternal A particle (IAP)-type family of endogenous retroviruses. Knockout of Mettl3 impairs the deposition of multiple heterochromatin marks onto METTL3-targeted IAPs, and upregulates IAP transcription, suggesting that METTL3 is important for the integrity of IAP heterochromatin. We provide further evidence that RNA transcripts derived from METTL3-bound IAPs are associated with chromatin and are m6A-methylated. These m6A-marked transcripts are bound by the m6A reader YTHDC1, which interacts with METTL3 and in turn promotes the association of METTL3 with chromatin. METTL3 also interacts physically with the histone 3 lysine 9 (H3K9) tri-methyltransferase SETDB1 and its cofactor TRIM28, and is important for their localization to IAPs. Our findings demonstrate that METTL3-catalysed m6A modification of RNA is important for the integrity of IAP heterochromatin in mouse embryonic stem cells, revealing a mechanism of heterochromatin regulation in mammals.Entities:
Year: 2021 PMID： 33505026 DOI： 10.1038/s41586-021-03210-1
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962