title: ERRα induces H3K9 demethylation by LSD1 to promote cell invasion.
abstract: Lysine Specific Demethylase 1 (LSD1) removes mono- and dimethyl groups from lysine 4 of histone H3 (H3K4) or H3K9, resulting in repressive or activating (respectively) transcriptional histone marks. The mechanisms that control the balance between these two antagonist activities are not understood. We here show that LSD1 and the orphan nuclear receptor estrogen-related receptor α (ERRα) display commonly activated genes. Transcriptional activation by LSD1 and ERRα involves H3K9 demethylation at the transcriptional start site (TSS). Strikingly, ERRα is sufficient to induce LSD1 to demethylate H3K9 in vitro. The relevance of this mechanism is highlighted by functional data. LSD1 and ERRα coregulate several target genes involved in cell migration, including the MMP1 matrix metallo-protease, also activated through H3K9 demethylation at the TSS. Depletion of LSD1 or ERRα reduces the cellular capacity to invade the extracellular matrix, a phenomenon that is rescued by MMP1 reexpression. Altogether our results identify a regulatory network involving a direct switch in the biochemical activities of a histone demethylase, leading to increased cell invasion.
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Carnesecchi
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Forcet
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.|Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Violaine
authors.initials: V
authors.lastname: Tribollet
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Barenton
authors.affiliation: Genetics, Reproduction and Development, Université Blaise Pascal Clermont-Ferrand, CNRS UMR 6293, Inserm U1103, Centre de Recherche en Nutrition Humaine, F-63171 Aubière, France.
authors.forename: Rafik
authors.initials: R
authors.lastname: Boudra
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cerutti
authors.affiliation: Department of Integrative Structural Biology, Institute of Genetics and Molecular and Cellular Biology, CNRS UMR7104, Inserm U964, Université de Strasbourg, F-67404 Illkirch, France.
authors.forename: Isabelle M L
authors.initials: IM
authors.lastname: Billas
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
authors.forename: Aurélien A
authors.initials: AA
authors.lastname: Sérandour
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.affiliation: Genetics, Reproduction and Development, Université Blaise Pascal Clermont-Ferrand, CNRS UMR 6293, Inserm U1103, Centre de Recherche en Nutrition Humaine, F-63171 Aubière, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Beaudoin
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France; jean-marc.vanacker@ens-lyon.fr.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Vanacker
mesh_terms: D002465:Cell Movement; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D056466:Histone Demethylases; D006657:Histones; D008239:Lysine; D020781:Matrix Metalloproteinase 1; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C495195:KDM1A protein, human; C522360:MMP1 protein, human
keywords: ERRα; LSD1; cell migration; histone demethylation; transcriptional regulation