Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming

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-...

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Published in:Cell stem cell 2015-12, Vol.17 (6), p.689-704
Main Authors: Aguilo, Francesca, Zhang, Fan, Sancho, Ana, Fidalgo, Miguel, Di Cecilia, Serena, Vashisht, Ajay, Lee, Dung-Fang, Chen, Chih-Hung, Rengasamy, Madhumitha, Andino, Blanca, Jahouh, Farid, Roman, Angel, Krig, Sheryl R, Wang, Rong, Zhang, Weijia, Wohlschlegel, James A, Wang, Jianlong, Walsh, Martin J
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
Cellular Reprogramming
DNA-Binding Proteins - metabolism
Embryonic Stem Cells - metabolism
Epigenesis, Genetic
Fibroblasts - metabolism
Gene Expression Regulation
Methyltransferases - metabolism
Mice
Pluripotent Stem Cells - metabolism
Promoter Regions, Genetic
Trans-Activators - metabolism
Transcriptome
Zinc Fingers
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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 (m(6)A) deposition on their transcripts by sequestering the enzyme m(6)A methyltransferase-like 3 (METTL3). Consistently, Zfp217 depletion compromises ESC self-renewal and somatic cell reprogramming, globally increases m(6)A RNA levels, and enhances m(6)A 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 m(6)A-modified transcripts. Collectively, these findings shed light on how a transcription factor can tightly couple gene transcription to m(6)A RNA modification to ensure ESC identity.
ISSN:1934-5909
1875-9777
1875-9777
DOI:10.1016/j.stem.2015.09.005