title: Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming.
abstract: While most somatic cells undergoing induced pluripotent stem (iPS) cell reprogramming with Yamanaka factors accumulate at stable partially reprogrammed stages, the molecular mechanisms required to achieve full reprogramming are unknown. MicroRNAs (miRNAs) fine-tune mRNA translation and are implicated in reprogramming, but miRNA functional targets critical for complete iPS cell reprogramming remain elusive. We identified methyl-DNA binding domain protein 2 (MBD2) as an epigenetic suppressor, blocking full reprogramming of somatic to iPS cells through direct binding to NANOG promoter elements preventing transcriptional activation. When we overexpressed miR-302 cluster we observed a significant increase in conversion of partial to fully reprogrammed iPS cells by suppressing MBD2 expression, thereby increasing NANOG expression. Thus, expression of exogenous miR-302 cluster (without miR-367) is efficient in attaining a fully reprogrammed iPS state in partially reprogrammed cells by relieving MBD2-mediated inhibition of NANOG expression. Our studies provide a direct molecular mechanism involved in generating complete human iPS cell reprogramming to study disease pathogenesis, drug screening, and for potential cell-based therapies.
authors.affiliation: Department of Microbiology and Immunology and Indiana University School of Medicine, Indianapolis, Indiana 46202-5181, USA.
authors.forename: Man Ryul
authors.initials: MR
authors.lastname: Lee
authors.forename: Nutan
authors.initials: N
authors.lastname: Prasain
authors.forename: Hee-Don
authors.initials: HD
authors.lastname: Chae
authors.forename: Young-June
authors.initials: YJ
authors.lastname: Kim
authors.forename: Charlie
authors.initials: C
authors.lastname: Mantel
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
mesh_terms: D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D000071317:Nanog Homeobox Protein
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein