title: Oocyte Factors Suppress Mitochondrial Polynucleotide Phosphorylase to Remodel the Metabolome and Enhance Reprogramming.
abstract: Oocyte factors not only drive somatic cell nuclear transfer reprogramming but also augment the efficiency and quality of induced pluripotent stem cell (iPSC) reprogramming. Here, we show that the oocyte-enriched factors Tcl1 and Tcl1b1 significantly enhance reprogramming efficiency. Clonal analysis of pluripotency biomarkers further show that the Tcl1 oocyte factors improve the quality of reprogramming. Mechanistically, we find that the enhancement effect of Tcl1b1 depends on Akt, one of its putative targets. In contrast, Tcl1 suppresses the mitochondrial polynucleotide phosphorylase (PnPase) to promote reprogramming. Knockdown of PnPase rescues the inhibitory effect from Tcl1 knockdown during reprogramming, whereas PnPase overexpression abrogates the enhancement from Tcl1 overexpression. We further demonstrate that Tcl1 suppresses PnPase's mitochondrial localization to inhibit mitochondrial biogenesis and oxidation phosphorylation, thus remodeling the metabolome. Hence, we identified the Tcl1-PnPase pathway as a critical mitochondrial switch during reprogramming.
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Swea-Ling
authors.initials: SL
authors.lastname: Khaw
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Chua
authors.initials: C
authors.lastname: Min-Wen
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore; Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore. Electronic address: cgkoh@ntu.edu.sg.
authors.forename: Cheng-Gee
authors.initials: CG
authors.lastname: Koh
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore. Electronic address: ngsc1@gis.a-star.edu.sg.
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D055442:Metabolome; D051379:Mice; D009865:Oocytes / Q000378:metabolism*; D001678:Organelle Biogenesis; D011117:Polyribonucleotide Nucleotidyltransferase / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D011117:Polyribonucleotide Nucleotidyltransferase