title: Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity.
abstract: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is characterized by extreme variability in symptoms, with females being less severely affected than males and presenting a higher proportion of asymptomatic carriers. The sex-related factors involved in the disease are not known. Here, we have utilized myoblasts isolated from FSHD patients (FSHD myoblasts) to investigate the effect of estrogens on muscle properties. Our results demonstrated that estrogens counteract the differentiation impairment of FSHD myoblasts without affecting cell proliferation or survival. Estrogen effects are mediated by estrogen receptor β (ERβ), which reduces chromatin occupancy and transcriptional activity of double homeobox 4 (DUX4), a protein whose aberrant expression has been implicated in FSHD pathogenesis. During myoblast differentiation, we observed that the levels and activity of DUX4 increased progressively and were associated with its enhanced recruitment in the nucleus. ERβ interfered with this recruitment by relocalizing DUX4 in the cytoplasm. This work identifies estrogens as a potential disease modifier that underlie sex-related differences in FSHD by protecting against myoblast differentiation impairments in this disease.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Teveroni
authors.forename: Marsha
authors.initials: M
authors.lastname: Pellegrino
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Calandra
authors.forename: Isabella
authors.initials: I
authors.lastname: Cascino
authors.forename: Stefano
authors.initials: S
authors.lastname: Farioli-Vecchioli
authors.forename: Angela
authors.initials: A
authors.lastname: Puma
authors.forename: Matteo
authors.initials: M
authors.lastname: Garibaldi
authors.forename: Roberta
authors.initials: R
authors.lastname: Morosetti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tasca
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Carlo Pietro
authors.initials: CP
authors.lastname: Trevisan
authors.forename: Giuliana
authors.initials: G
authors.lastname: Galluzzi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pontecorvi
authors.forename: Marco
authors.initials: M
authors.lastname: Crescenzi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Deidda
authors.forename: Fabiola
authors.initials: F
authors.lastname: Moretti
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D004958:Estradiol / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000378:metabolism* / Q000473:pathology; D032446:Myoblasts / Q000502:physiology*; D021381:Protein Transport; D015533:Transcriptional Activation
chemical_list: C121257:DUX4L1 protein, human; C000600034:ESR2 protein, human; D047629:Estrogen Receptor beta; D004967:Estrogens; D018398:Homeodomain Proteins; D004958:Estradiol