title: Inactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4.
abstract: Coordination of energy metabolism is essential for homeostasis of stem cells, whereas an imbalance in energy homeostasis causes disease and accelerated aging. Here we show that deletion or enzymatic inactivation of lysine-specific demethylase 1 (Lsd1) triggers senescence in trophoblast stem cells (TSCs). Genome-wide transcriptional profiling of TSCs following Lsd1 inhibition shows gene set enrichment of aging and metabolic pathways. Consistently, global metabolomic and phenotypic analyses disclose an unbalanced redox status, decreased glutamine anaplerosis and mitochondrial function. Loss of homeostasis is caused by increased expression of sirtuin 4 (Sirt4), a Lsd1-repressed direct target gene. Accordingly, Sirt4 overexpression in wild-type TSCs recapitulates the senescence phenotype initiated by Lsd1 deletion or inhibition. Inversely, absence of Lsd1 enzymatic activity concomitant with knockdown of Sirt4 reestablishes normal glutamine anaplerosis, redox balance and mitochondrial function. In conclusion, by repression of Sirt4, Lsd1 directs the epigenetic control of TSC immortality via maintenance of metabolic flexibility.
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Josefina
authors.initials: J
authors.lastname: Castex
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Dominica
authors.initials: D
authors.lastname: Willmann
authors.affiliation: Celgene Quanticel Research, San Diego, CA, USA.
authors.forename: Toufike
authors.initials: T
authors.lastname: Kanouni
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Arrigoni
authors.affiliation: metaSysX GmbH, Potsdam-Golm, Germany.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Friedrich
authors.affiliation: Boehringer Ingelheim, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schleicher
authors.affiliation: Boehringer Ingelheim, Vienna, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Wöhrle
authors.affiliation: Boehringer Ingelheim, Vienna, Austria.
authors.forename: Mark
authors.initials: M
authors.lastname: Pearson
authors.affiliation: Boehringer Ingelheim, Vienna, Austria.
authors.forename: Norbert
authors.initials: N
authors.lastname: Kraut
authors.affiliation: metaSysX GmbH, Potsdam-Golm, Germany.
authors.forename: Michaël
authors.initials: M
authors.lastname: Méret
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Thomas
authors.identifier: 0000-0003-3702-0868
authors.initials: T
authors.lastname: Manke
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.|Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg, Freiburg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.|Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg, Freiburg, Germany.|BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Günther
mesh_terms: D000375:Aging / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology*; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D037761:Sirtuins / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism* / Q000502:physiology; D014327:Trophoblasts / Q000378:metabolism* / Q000502:physiology
chemical_list: D024101:Mitochondrial Proteins; D056466:Histone Demethylases; D037761:Sirtuins