METTL3 regulates heterochromatin in mouse embryonic stem cells

Wenqi Xu, Jiahui Li, Chenxi He, Jing Wen, Honghui Ma, Bowen Rong, Jianbo Diao, Liyong Wang, Jiahua Wang, Feizhen Wu, Li Tan, Yujiang Geno Shi, Yang Shi () and Hongjie Shen ()
Additional contact information
Wenqi Xu: Fudan University
Jiahui Li: Fudan University
Chenxi He: Fudan University
Jing Wen: Fudan University
Honghui Ma: Fudan University
Bowen Rong: Fudan University
Jianbo Diao: Fudan University
Liyong Wang: Fudan University
Jiahua Wang: Fudan University
Feizhen Wu: Fudan University
Li Tan: Fudan University
Yujiang Geno Shi: Harvard Medical School
Yang Shi: University of Oxford
Hongjie Shen: Fudan University

Nature, 2021, vol. 591, issue 7849, 317-321

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (8)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03210-1 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:591:y:2021:i:7849:d:10.1038_s41586-021-03210-1

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03210-1

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().