title: Identification of Oct4-activating compounds that enhance reprogramming efficiency.
abstract: One of the hurdles for practical application of induced pluripotent stem cells (iPSC) is the low efficiency and slow process of reprogramming. Octamer-binding transcription factor 4 (Oct4) has been shown to be an essential regulator of embryonic stem cell (ESC) pluripotency and key to the reprogramming process. To identify small molecules that enhance reprogramming efficiency, we performed a cell-based high-throughput screening of chemical libraries. One of the compounds, termed Oct4-activating compound 1 (OAC1), was found to activate both Oct4 and Nanog promoter-driven luciferase reporter genes. Furthermore, when added to the reprogramming mixture along with the quartet reprogramming factors (Oct4, Sox2, c-Myc, and Klf4), OAC1 enhanced the iPSC reprogramming efficiency and accelerated the reprogramming process. Two structural analogs of OAC1 also activated Oct4 and Nanog promoters and enhanced iPSC formation. The iPSC colonies derived using the Oct4-activating compounds along with the quartet factors exhibited typical ESC morphology, gene-expression pattern, and developmental potential. OAC1 seems to enhance reprogramming efficiency in a unique manner, independent of either inhibition of the p53-p21 pathway or activation of the Wnt-β-catenin signaling. OAC1 increases transcription of the Oct4-Nanog-Sox2 triad and Tet1, a gene known to be involved in DNA demethylation.
authors.affiliation: Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Wendong
authors.initials: W
authors.lastname: Li
authors.forename: E
authors.initials: E
authors.lastname: Tian
authors.forename: Zhao-Xia
authors.initials: ZX
authors.lastname: Chen
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Sun
authors.forename: Peng
authors.initials: P
authors.lastname: Ye
authors.forename: Su
authors.initials: S
authors.lastname: Yang
authors.forename: Dave
authors.initials: D
authors.lastname: Lu
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Thach-Vu
authors.initials: TV
authors.lastname: Ho
authors.forename: Walter M
authors.initials: WM
authors.lastname: Tsark
authors.forename: Charles
authors.initials: C
authors.lastname: Wang
authors.forename: David A
authors.initials: DA
authors.lastname: Horne
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Riggs
authors.forename: M L Richard
authors.initials: ML
authors.lastname: Yip
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation; D065150:Cellular Reprogramming / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015195:Drug Design; D053595:Embryonic Stem Cells / Q000166:cytology*; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D006899:Mixed Function Oxygenases; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism
chemical_list: D001549:Benzamides; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011758:Pyrroles; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C540839:TET1 protein, mouse; D049452:Green Fluorescent Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human