title: Zfp281 functions as a transcriptional repressor for pluripotency of mouse embryonic stem cells.
abstract: Embryonic stem cells (ESCs) derived from preimplantation blastocysts have unique self-renewal and multilineage differentiation properties that are controlled by key components of a core regulatory network including Oct4, Sox2, and Nanog. Understanding molecular underpinnings of these properties requires identification and characterization of additional factors that act in conjunction with these key factors in ESCs. We have previously identified Zfp281, a Krüppel-like zinc finger transcription factor, as an interaction partner of Nanog. We now present detailed functional analyses of Zfp281 using a genetically ablated null allele in mouse ESCs. Our data show that while Zfp281 is dispensable for establishment and maintenance of ESCs, it is required for their proper differentiation in vitro. We performed microarray profiling in combination with previously published datasets of Zfp281 global target gene occupancy and found that Zfp281 mainly functions as a repressor to restrict expression of many stem cell pluripotency genes. In particular, we demonstrated that deletion of Zfp281 resulted in upregulation of Nanog at both the transcript and protein levels with concomitant compromised differentiation of ESCs during embryoid body culture. Chromatin immunoprecipitation experiments demonstrated that Zfp281 is required for Nanog binding to its own promoter, suggesting that Nanog-associated repressive complex(es) involving Zfp281 may fine-tune Nanog expression for pluripotency of ESCs.
authors.affiliation: Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York 10029, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fidalgo
authors.forename: P Chandra
authors.initials: PC
authors.lastname: Shekar
authors.forename: Yen-Sin
authors.initials: YS
authors.lastname: Ang
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D014157:Transcription Factors; C540267:Zfp281 protein, mouse