title: Reprogramming of postnatal neurons into induced pluripotent stem cells by defined factors.
abstract: Pluripotent cells can be derived from different types of somatic cells by nuclear reprogramming through the ectopic expression of four transcription factors, Oct3/4, Sox2, Klf4, and c-Myc. However, it is unclear whether postmitotic neurons are susceptible to direct reprogramming. Here, we show that postnatal cortical neurons, the vast majority of which are postmitotic, are amenable to epigenetic reprogramming. However, ectopic expression of the four canonical reprogramming factors is not sufficient to reprogram postnatal neurons. Efficient reprogramming was only achieved after forced cell proliferation by p53 suppression. Additionally, overexpression of repressor element-1 silencing transcription, a suppressor of neuronal gene activity, increased reprogramming efficiencies in combination with the reprogramming factors. Our findings indicate that terminally differentiated postnatal neurons are able to acquire the pluripotent state by direct epigenetic reprogramming, and this process is made more efficient through the suppression of lineage specific gene expression.
authors.affiliation: Whitehead Institute for Biomedical Research and, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jongpil
authors.initials: J
authors.lastname: Kim
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.forename: Oktay
authors.initials: O
authors.lastname: Kirak
authors.forename: Jacob
authors.initials: J
authors.lastname: Hanna
authors.forename: John P
authors.initials: JP
authors.lastname: Cassady
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lodato
authors.forename: Su
authors.initials: S
authors.lastname: Wu
authors.forename: Dina A
authors.initials: DA
authors.lastname: Faddah
authors.forename: Eveline J
authors.initials: EJ
authors.lastname: Steine
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.forename: Dongdong
authors.initials: D
authors.lastname: Fu
authors.forename: Meelad
authors.initials: M
authors.lastname: Dawlaty
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001755:Blastocyst / Q000166:cytology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004624:Embryo Transfer; D005347:Fibroblasts / Q000166:cytology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D000090062:Kruppel-Like Factor 4; D016256:Lewis X Antigen / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D013724:Teratoma / Q000473:pathology; D018183:Transplantation Chimera; D000099229:RE1-Silencing Transcription Factor
chemical_list: D015415:Biomarkers; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D000090062:Kruppel-Like Factor 4; D016256:Lewis X Antigen; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C000715468:Klf4 protein, mouse; C475540:Nanog protein, mouse; C494174:Pou5f1 protein, mouse