title: LSD1 modulates stress-evoked transcription of immediate early genes and emotional behavior.
abstract: Behavioral changes in response to stressful stimuli can be controlled via adaptive epigenetic changes in neuronal gene expression. Here we indicate a role for the transcriptional corepressor Lysine-Specific Demethylase 1 (LSD1) and its dominant-negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In mouse hippocampus, we show that LSD1 and neuroLSD1 can interact with transcription factor serum response factor (SRF) and set the chromatin state of SRF-targeted genes early growth response 1 (egr1) and c-fos Deletion or reduction of neuro LSD1 in mutant mice translates into decreased levels of activating histone marks at egr1 and c-fos promoters, dampening their psychosocial stress-induced transcription and resulting in low anxiety-like behavior. Administration of suberoylanilide hydroxamine to neuroLSD1(KO)mice reactivates egr1 and c-fos transcription and restores the behavioral phenotype. These findings indicate that LSD1 is a molecular transducer of stressful stimuli as well as a stress-response modifier. Indeed, LSD1 expression itself is increased acutely at both the transcriptional and splicing levels by psychosocial stress, suggesting that LSD1 is involved in the adaptive response to stress.
authors.affiliation: Laboratory of Neuroepigenetics, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale and Centro di Eccellenza per le Malattie Neurodegenerative (CEND), Università degli Studi di Milano, 20133 Milan, Italy; Francesco.rusconi@unimi.it elena.battaglioli@unimi.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rusconi
authors.affiliation: Laboratory of Neuroepigenetics, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale and Centro di Eccellenza per le Malattie Neurodegenerative (CEND), Università degli Studi di Milano, 20133 Milan, Italy;
authors.forename: Barbara
authors.initials: B
authors.lastname: Grillo
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, 20129 Milan, Italy;
authors.forename: Luisa
authors.initials: L
authors.lastname: Ponzoni
authors.affiliation: National Research Council Institute of Neuroscience, 20129 Milan, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Bassani
authors.affiliation: Laboratory of Neuroepigenetics, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale and Centro di Eccellenza per le Malattie Neurodegenerative (CEND), Università degli Studi di Milano, 20133 Milan, Italy;
authors.forename: Emanuela
authors.initials: E
authors.lastname: Toffolo
authors.affiliation: Laboratory of Neuroepigenetics, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale and Centro di Eccellenza per le Malattie Neurodegenerative (CEND), Università degli Studi di Milano, 20133 Milan, Italy;
authors.forename: Leda
authors.initials: L
authors.lastname: Paganini
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Università degli Studi di Milano, 20133 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mallei
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, 20129 Milan, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Braida
authors.affiliation: National Research Council Institute of Neuroscience, 20129 Milan, Italy;
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Università degli Studi di Milano, 20133 Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Popoli
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, 20129 Milan, Italy; National Research Council Institute of Neuroscience, 20129 Milan, Italy;
authors.forename: Mariaelvina
authors.initials: M
authors.lastname: Sala
authors.affiliation: Laboratory of Neuroepigenetics, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale and Centro di Eccellenza per le Malattie Neurodegenerative (CEND), Università degli Studi di Milano, 20133 Milan, Italy; National Research Council Institute of Neuroscience, 20129 Milan, Italy; Francesco.rusconi@unimi.it elena.battaglioli@unimi.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Battaglioli
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D051766:Early Growth Response Protein 1 / Q000235:genetics; D004644:Emotions / Q000502:physiology*; D044127:Epigenesis, Genetic; D017781:Genes, Immediate-Early; D016762:Genes, fos; D056466:Histone Demethylases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009473:Neuronal Plasticity; D010641:Phenotype; D026362:Serum Response Factor / Q000502:physiology; D013315:Stress, Psychological; D014158:Transcription, Genetic
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D026362:Serum Response Factor; D056466:Histone Demethylases; C504076:KDM1a protein, mouse
keywords: LSD1; SRF; epigenetics; immediate early genes; stress