title: Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming.
abstract: The homeodomain transcription factor Nanog plays an important role in embryonic stem cell (ESC) self-renewal and is essential for acquiring ground-state pluripotency during reprogramming. Understanding how Nanog is transcriptionally regulated is important for further dissecting mechanisms of ESC pluripotency and somatic cell reprogramming. Here, we report that Nanog is subjected to a negative autoregulatory mechanism, i.e., autorepression, in ESCs, and that such autorepression requires the coordinated action of the Nanog partner and transcriptional repressor Zfp281. Mechanistically, Zfp281 recruits the NuRD repressor complex onto the Nanog locus and maintains its integrity to mediate Nanog autorepression and, functionally, Zfp281-mediated Nanog autorepression presents a roadblock to efficient somatic cell reprogramming. Our results identify a unique transcriptional regulatory mode of Nanog gene expression and shed light into the mechanistic understanding of Nanog function in pluripotency and reprogramming.
authors.affiliation: Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, and The Graduate School of Biological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fidalgo
authors.forename: Francesco
authors.initials: F
authors.lastname: Faiola
authors.forename: Carlos-Filipe
authors.initials: CF
authors.lastname: Pereira
authors.forename: Junjun
authors.initials: J
authors.lastname: Ding
authors.forename: Arven
authors.initials: A
authors.lastname: Saunders
authors.forename: Julian
authors.initials: J
authors.lastname: Gingold
authors.forename: Christoph
authors.initials: C
authors.lastname: Schaniel
authors.forename: Ihor R
authors.initials: IR
authors.lastname: Lemischka
authors.forename: José C R
authors.initials: JC
authors.lastname: Silva
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D065150:Cellular Reprogramming / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D047468:Immunoprecipitation; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D051379:Mice; D000071317:Nanog Homeobox Protein; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D014157:Transcription Factors; C540267:Zfp281 protein, mouse; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex