title: Zfp281 Coordinates Opposing Functions of Tet1 and Tet2 in Pluripotent States.
abstract: Pluripotency is increasingly recognized as a spectrum of cell states defined by their growth conditions. Although naive and primed pluripotency states have been characterized molecularly, our understanding of events regulating state acquisition is wanting. Here, we performed comparative RNA sequencing of mouse embryonic stem cells (ESCs) and defined a pluripotent cell fate (PCF) gene signature associated with acquisition of naive and primed pluripotency. We identify Zfp281 as a key transcriptional regulator for primed pluripotency that also functions as a barrier toward achieving naive pluripotency in both mouse and human ESCs. Mechanistically, Zfp281 interacts with Tet1, but not Tet2, and its direct transcriptional target, miR-302/367, to negatively regulate Tet2 expression to establish and maintain primed pluripotency. Conversely, ectopic Tet2 alone, but not Tet1, efficiently reprograms primed cells toward naive pluripotency. Our study reveals a molecular circuitry in which opposing functions of Tet1 and Tet2 control acquisition of alternative pluripotent states.
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Departamento de Fisioloxia, Centro de Investigacion en Medicina Molecular e Enfermidades Cronicas, Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fidalgo
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Guallar
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sanchez-Priego
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Victor Julian
authors.initials: VJ
authors.lastname: Valdes
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Arven
authors.initials: A
authors.lastname: Saunders
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Junjun
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Wen-Shu
authors.initials: WS
authors.lastname: Wu
authors.affiliation: Hair and Pigmentation Development, A(∗)Star-Institute of Medical Biology, 138648 Singapore, Singapore.
authors.forename: Carlos
authors.initials: C
authors.lastname: Clavel
authors.affiliation: The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: jianlong.wang@mssm.edu.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001483:Base Sequence; D019070:Cell Lineage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; D014157:Transcription Factors; C540267:Zfp281 protein, mouse; D049308:Dioxygenases; C551914:Tet2 protein, mouse
keywords: ESCs; EpiSCs; ZNF281; miR-302/367 cluster; naive; primed