title: HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles.
abstract: Fibro-adipogenic progenitors (FAPs) are important components of the skeletal muscle regenerative environment. Whether FAPs support muscle regeneration or promote fibro-adipogenic degeneration is emerging as a key determinant in the pathogenesis of muscular diseases, including Duchenne muscular dystrophy (DMD). However, the molecular mechanism that controls FAP lineage commitment and activity is currently unknown. We show here that an HDAC-myomiR-BAF60 variant network regulates the fate of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray, genome-wide chromatin remodeling by nuclease accessibility (NA) combined with next-generation sequencing (NA-seq), small RNA sequencing (RNA-seq), and microRNA (miR) high-throughput screening (HTS) against SWI/SNF BAF60 variants revealed that HDAC inhibitors (HDACis) derepress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease. Specifically, HDAC inhibition induces two core components of the myogenic transcriptional machinery, MYOD and BAF60C, and up-regulates the myogenic miRs (myomiRs) (miR-1.2, miR-133, and miR-206), which target the alternative BAF60 variants BAF60A and BAF60B, ultimately directing promyogenic differentiation while suppressing the fibro-adipogenic phenotype. In contrast, FAPs from late stage dystrophic muscles are resistant to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the promyogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bipotency by epigenetic intervention with HDACis provides a molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles.
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00143 Rome, Italy;
authors.forename: Valentina
authors.initials: V
authors.lastname: Saccone
authors.forename: Silvia
authors.initials: S
authors.lastname: Consalvi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Giordani
authors.forename: Chiara
authors.initials: C
authors.lastname: Mozzetta
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.forename: Martina
authors.initials: M
authors.lastname: Sandoná
authors.forename: Tammy
authors.initials: T
authors.lastname: Ryan
authors.forename: Agustin
authors.initials: A
authors.lastname: Rojas-Muñoz
authors.forename: Luca
authors.initials: L
authors.lastname: Madaro
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fasanaro
authors.forename: Giovanna
authors.initials: G
authors.lastname: Borsellino
authors.forename: Marco
authors.initials: M
authors.lastname: De Bardi
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Frigè
authors.forename: Alberto
authors.initials: A
authors.lastname: Termanini
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D018101:Mice, Inbred mdx; D035683:MicroRNAs / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000503:physiopathology*; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D035683:MicroRNAs; D009124:Muscle Proteins; C529549:Smarcd1 protein, mouse; C494056:Smarcd2 protein, mouse; C012589:trichostatin A; D006655:Histone Deacetylases
keywords: BAF60; FAPs; HDAC; SWI/SNF chromatin remodeling; microRNA; muscular dystrophy