title: TRIM32 modulates pluripotency entry and exit by directly regulating Oct4 stability.
abstract: Induced pluripotent stem cells (iPSCs) have revolutionized the world of regenerative medicine; nevertheless, the exact molecular mechanisms underlying their generation and differentiation remain elusive. Here, we investigated the role of the cell fate determinant TRIM32 in modulating such processes. TRIM32 is essential for the induction of neuronal differentiation of neural stem cells by poly-ubiquitinating cMyc to target it for degradation resulting in inhibition of cell proliferation. To elucidate the role of TRIM32 in regulating somatic cell reprogramming we analysed the capacity of TRIM32-knock-out mouse embryonic fibroblasts (MEFs) in generating iPSC colonies. TRIM32 knock-out MEFs produced a higher number of iPSC colonies indicating a role for TRIM32 in inhibiting this cellular transition. Further characterization of the generated iPSCs indicated that the TRIM32 knock-out iPSCs show perturbed differentiation kinetics. Additionally, mathematical modelling of global gene expression data revealed that during differentiation an Oct4 centred network in the wild-type cells is replaced by an E2F1 centred network in the TRIM32 deficient cells. We show here that this might be caused by a TRIM32-dependent downregulation of Oct4. In summary, the data presented here reveal that TRIM32 directly regulates at least two of the four Yamanaka Factors (cMyc and Oct4), to modulate cell fate transitions.
authors: Westfälische Wilhelms-Universität Münster, ZMBE, Institute of Cell Biology, Stem Cell Biology and Regeneration Group, Von-Esmarch-Str. 56, 48149 Münster, Germany.|Luxembourg Centre for Systems Biomedicine (LCSB), Developmental and Cellular Biology, University of Luxembourg, 7 avenue des Hauts-Fourneaux, 4362 Esch-Belval, Luxembourg.
authors: Lamia'a
authors: L
authors: Bahnassawy
authors: Luxembourg Centre for Systems Biomedicine (LCSB), Computational Biology, University of Luxembourg, 7 avenue des Hauts-Fourneaux, 4362 Esch-Belval, Luxembourg.
authors: Thanneer M
authors: TM
authors: Perumal
authors: Luxembourg Centre for Systems Biomedicine (LCSB), Developmental and Cellular Biology, University of Luxembourg, 7 avenue des Hauts-Fourneaux, 4362 Esch-Belval, Luxembourg.
authors: Laura
authors: L
authors: Gonzalez-Cano
authors: Luxembourg Centre for Systems Biomedicine (LCSB), Developmental and Cellular Biology, University of Luxembourg, 7 avenue des Hauts-Fourneaux, 4362 Esch-Belval, Luxembourg.
authors: Anna-Lena
authors: AL
authors: Hillje
authors: Institute for Biostatistics and Informatics in Medicine und Ageing Research, Rostock University Medical Centre, Ernst-Heydemann-Str. 8, 18057 Rostock, Germany.
authors: Leila
authors: L
authors: Taher
authors: Westfälische Wilhelms-Universität Münster, Institute of Bioinformatics, Niels-Stensen-Straße 14, 48149 Münster, Germany.
authors: Wojciech
authors: W
authors: Makalowski
authors: Department of Medical Genome Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa-shi, Chiba-ken 227-8561, Japan.
authors: Yutaka
authors: Y
authors: Suzuki
authors: Institute for Biostatistics and Informatics in Medicine und Ageing Research, Rostock University Medical Centre, Ernst-Heydemann-Str. 8, 18057 Rostock, Germany.
authors: Georg
authors: G
authors: Fuellen
authors: Luxembourg Centre for Systems Biomedicine (LCSB), Computational Biology, University of Luxembourg, 7 avenue des Hauts-Fourneaux, 4362 Esch-Belval, Luxembourg.
authors: Antonio
authors: A
authors: del Sol
authors: Westfälische Wilhelms-Universität Münster, ZMBE, Institute of Cell Biology, Stem Cell Biology and Regeneration Group, Von-Esmarch-Str. 56, 48149 Münster, Germany.|Luxembourg Centre for Systems Biomedicine (LCSB), Developmental and Cellular Biology, University of Luxembourg, 7 avenue des Hauts-Fourneaux, 4362 Esch-Belval, Luxembourg.
authors: Jens Christian
authors: JC
authors: Schwamborn
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases