title: Collaborative rewiring of the pluripotency network by chromatin and signalling modulating pathways.
abstract: Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) represents a profound change in cell fate. Here, we show that combining ascorbic acid (AA) and 2i (MAP kinase and GSK inhibitors) increases the efficiency of reprogramming from fibroblasts and synergistically enhances conversion of partially reprogrammed intermediates to the iPSC state. AA and 2i induce differential transcriptional responses, each leading to the activation of specific pluripotency loci. A unique cohort of pluripotency genes including Esrrb require both stimuli for activation. Temporally, AA-dependent histone demethylase effects are important early, whereas Tet enzyme effects are required throughout the conversion. 2i function could partially be replaced by depletion of components of the epidermal growth factor (EGF) and insulin growth factor pathways, indicating that they act as barriers to reprogramming. Accordingly, reduction in the levels of the EGF receptor gene contributes to the activation of Esrrb. These results provide insight into the rewiring of the pluripotency network at the late stage of reprogramming.
authors: 1] Wisconsin Institute for Discovery, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA [2] Molecular and Cellular Pharmacology Program, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA.
authors: Khoa A
authors: KA
authors: Tran
authors: Wisconsin Institute for Discovery, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA.
authors: Steven A
authors: SA
authors: Jackson
authors: Wisconsin Institute for Discovery, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA.
authors: Zachariah P G
authors: ZP
authors: Olufs
authors: Wisconsin Institute for Discovery, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA.
authors: Nur Zafirah
authors: NZ
authors: Zaidan
authors: Department of Statistics, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA.
authors: Ning
authors: N
authors: Leng
authors: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA.
authors: Christina
authors: C
authors: Kendziorski
authors: 1] Wisconsin Institute for Discovery, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA [2] Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA.
authors: Sushmita
authors: S
authors: Roy
authors: 1] Wisconsin Institute for Discovery, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA [2] Department of Cell and Regenerative Biology, University of Wisconsin, Madison, 330 N. Orchard Street, Room 2118, Wisconsin 53715, USA.
authors: Rupa
authors: R
authors: Sridharan
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D065150:Cellular Reprogramming / Q000187:drug effects; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004622:Embryo, Mammalian; D004815:Epidermal Growth Factor / Q000172:deficiency / Q000235:genetics; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053263:Gene Regulatory Networks / Q000187:drug effects; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000172:deficiency / Q000235:genetics
chemical_list: D002843:Chromatin; C098925:Esrrb protein, mouse; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D013002:Somatomedins; D049452:Green Fluorescent Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D001205:Ascorbic Acid
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