Coordination of m6A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming

Francesca Aguilo, Fan Zhang, Ana Sancho, Miguel Fidalgo, Serena Di Cecilia, Ajay Vashisht, Dung Fang Lee, Chih Hung Chen, Madhumitha Rengasamy, Blanca Andino, Farid Jahouh, Angel Roman, Sheryl R. Krig, Rong Wang, Weijia Zhang, James A. Wohlschlegel, Jianlong Wang, Martin J. Walsh

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

Summary Epigenetic and epitranscriptomic networks have important functions in maintaining the pluripotency of embryonic stem cells (ESCs) and somatic cell reprogramming. However, the mechanisms integrating the actions of these distinct networks are only partially understood. Here we show that the chromatin-associated zinc finger protein 217 (ZFP217) coordinates epigenetic and epitranscriptomic regulation. ZFP217 interacts with several epigenetic regulators, activates the transcription of key pluripotency genes, and modulates N6-methyladenosine (m6A) deposition on their transcripts by sequestering the enzyme m6A methyltransferase-like 3 (METTL3). Consistently, Zfp217 depletion compromises ESC self-renewal and somatic cell reprogramming, globally increases m6A RNA levels, and enhances m6A modification of the Nanog, Sox2, Klf4, and c-Myc mRNAs, promoting their degradation. ZFP217 binds its own target gene mRNAs, which are also METTL3 associated, and is enriched at promoters of m6A-modified transcripts. Collectively, these findings shed light on how a transcription factor can tightly couple gene transcription to m6A RNA modification to ensure ESC identity.

Original languageEnglish
Pages (from-to)689-704
Number of pages16
JournalCell Stem Cell
Volume17
Issue number6
DOIs
StatePublished - 3 Dec 2015

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