title: Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency.
abstract: Transcription factor Stat3 directs self-renewal of pluripotent mouse embryonic stem (ES) cells downstream of the cytokine leukemia inhibitory factor (LIF). Stat3 upregulates pivotal transcription factors in the ES cell gene regulatory network to sustain naïve identity. Stat3 also contributes to the rapid proliferation of ES cells. Here, we show that Stat3 increases the expression of mitochondrial-encoded transcripts and enhances oxidative metabolism. Chromatin immunoprecipitation reveals that Stat3 binds to the mitochondrial genome, consistent with direct transcriptional regulation. An engineered form of Stat3 that localizes predominantly to mitochondria is sufficient to support enhanced proliferation of ES cells, but not to maintain their undifferentiated phenotype. Furthermore, during reprogramming from primed to naïve states of pluripotency, Stat3 similarly upregulates mitochondrial transcripts and facilitates metabolic resetting. These findings suggest that the potent stimulation of naïve pluripotency by LIF/Stat3 is attributable to parallel and synergistic induction of both mitochondrial respiration and nuclear transcription factors.
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Carbognin
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy.
authors.forename: Riccardo M
authors.initials: RM
authors.lastname: Betto
authors.affiliation: Department of Biology, University of Padua, Padua, Italy.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Soriano
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK Department of Biochemistry, University of Cambridge, Cambridge, UK austin.smith@cscr.cam.ac.uk graziano.martello@unipd.it.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Smith
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy austin.smith@cscr.cam.ac.uk graziano.martello@unipd.it.
authors.forename: Graziano
authors.initials: G
authors.lastname: Martello
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D019069:Cell Respiration; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: LIF; Stat3; metabolism; mitochondrial respiration; pluripotency