PXD056046

PXD056046 is an original dataset announced via ProteomeXchange.

Title	METTL3-dependent m6A RNA Methylation Regulates Transposable Elements and Represses Human Naïve Pluripotency through Transposable Element-derived Enhancers
Description	N6-methyladenosine (m6A) is the most prevalent mRNA modification with diverse regulatory roles in mammalian cells. While its functions are well-documented in mouse embryonic stem cells (mESCs), its role in human pluripotent stem cells (hPSCs) remains to be fully explored. METTL3 is the main enzyme responsible for m6A deposition. Here, using a METTL3 inducible knockout (iKO) system, we uncovered that, unlike in mESCs, METTL3 was indispensable for hPSC maintenance. Importantly, loss of METTL3 caused significant upregulation of pluripotency factors including naïve pluripotency genes and failure to exit pluripotency, thus impaired stem cell differentiation towards embryonic and extraembryonic cells including trophoblasts. Mechanistically, METTL3 iKO in hPSCs substantially increased expression and enhancer activities of two primate-specific transposable elements (TEs), SVA_D and HERVK/LTR5_Hs, which are normally modified by METTL3-dependent m6A. METTL3 loss activated SVA_D by lowering H3K9me3 deposition, and increased chromatin accessibility at LTR5_Hs through the naïve and other pluripotency factors. Conversely, we discovered that the activated SVA_D and LTR5_Hs loci positively regulated naïve gene expression by directly interacted with their promoters. These findings thus reveal that METTL3-dependent m6A RNA methylation has critical roles in suppressing TE expression and in the human pluripotency regulatory network.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_02:55:45.018.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Haifeng Fu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-20 01:47:21	ID requested
⏵ 1	2025-05-07 02:55:45	announced

10.1093/nar/gkaf349;

Zhang W, Fu H, Huang Y, Zeng M, Ouyang X, Wang X, Ruan D, Ma L, Hu X, Guo J, Galardi JW, Dougan G, Yeung WSB, Li L, Liu J, Feschotte C, Liu P, ve pluripotency through transposable element-derived enhancers. Nucleic Acids Res, 53(8):(2025) [pubmed]

submitter keyword: hEPSCs, METTL3, LC-MS/MS

Pengtao Liu
contact affiliation	1. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China. 2. Centre for Translational Stem Cell Biology, The University of Hong Kong, Hong Kong Special Administrative Region, China.
contact email	pliu88@hku.hk
lab head
Haifeng Fu
contact affiliation	The University of Hong Kong
contact email	hffu89@hku.hk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD056046

PRIDE project URI

• PRIDE
  1. PXD056046
     1. Label: PRIDE project
     2. Name: METTL3-dependent m6A RNA Methylation Regulates Transposable Elements and Represses Human Naïve Pluripotency through Transposable Element-derived Enhancers