title: Polycomb repressive complex 1 provides a molecular explanation for repeat copy number dependency in FSHD muscular dystrophy.
abstract: Repression of repetitive elements is crucial to preserve genome integrity and has been traditionally ascribed to constitutive heterochromatin pathways. FacioScapuloHumeral Muscular Dystrophy (FSHD), one of the most common myopathies, is characterized by a complex interplay of genetic and epigenetic events. The main FSHD form is linked to a reduced copy number of the D4Z4 macrosatellite repeat on 4q35, causing loss of silencing and aberrant expression of the D4Z4-embedded DUX4 gene leading to disease. By an unknown mechanism, D4Z4 copy-number correlates with FSHD phenotype. Here we show that the DUX4 proximal promoter (DUX4p) is sufficient to nucleate the enrichment of both constitutive and facultative heterochromatin components and to mediate a copy-number dependent gene silencing. We found that both the CpG/GC dense DNA content and the repetitive nature of DUX4p arrays are important for their repressive ability. We showed that DUX4p mediates a copy number-dependent Polycomb Repressive Complex 1 (PRC1) recruitment, which is responsible for the copy-number dependent gene repression. Overall, we directly link genetic and epigenetic defects in FSHD by proposing a novel molecular explanation for the copy number-dependency in FSHD pathogenesis, and offer insight into the molecular functions of repeats in chromatin regulation.
authors.affiliation: Gene Expression and Muscular Dystrophy Unit, Division of Regenerative Medicine, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|Università Vita-Salute San Raffaele, Milan 20132, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Casa
authors.affiliation: Gene Expression and Muscular Dystrophy Unit, Division of Regenerative Medicine, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Runfola
authors.affiliation: Gene Expression and Muscular Dystrophy Unit, Division of Regenerative Medicine, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Micheloni
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
authors.forename: Arif
authors.initials: A
authors.lastname: Aziz
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
authors.forename: F Jeffrey
authors.initials: FJ
authors.lastname: Dilworth
authors.affiliation: Gene Expression and Muscular Dystrophy Unit, Division of Regenerative Medicine, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.|Dulbecco Telethon Institute, Milan 20132, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Gabellini
mesh_terms: D002460:Cell Line; D056915:DNA Copy Number Variations; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018895:Microsatellite Repeats; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D063150:Polycomb Repressive Complex 1