title: Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming.
abstract: 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.
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: francesca.aguilo@mssm.edu.
authors.forename: Francesca
authors.initials: F
authors.lastname: Aguilo
authors.affiliation: Bioinformatics Laboratory, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Sancho
authors.affiliation: Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fidalgo
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Cecilia
authors.affiliation: Department of Biological Chemistry and Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vashisht
authors.affiliation: Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Madhumitha
authors.initials: M
authors.lastname: Rengasamy
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Blanca
authors.initials: B
authors.lastname: Andino
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Farid
authors.initials: F
authors.lastname: Jahouh
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Roman
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Sheryl R
authors.initials: SR
authors.lastname: Krig
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Bioinformatics Laboratory, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Biological Chemistry and Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Wohlschlegel
authors.affiliation: Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: martin.walsh@mssm.edu.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D000090062:Kruppel-Like Factor 4; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism*; D059467:Transcriptome; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D015534:Trans-Activators; C000611571:ZFP217 protein, mouse; D008780:Methyltransferases; C000596366:Mettl3 protein, mouse