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HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibroadipogenic progenitors in dystrophic muscles

ABSTRACT: Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration – is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an “HDAC-myomiR-BAF60 variant network” regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a “latent” myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) 1.2, 133 and 206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles.

ORGANISM(S): Mus musculus

PROVIDER: GSE52062 | GEO | 2014/04/02

SECONDARY ACCESSION(S): PRJNA226605

REPOSITORIES: GEO

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Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration - is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an "HDAC-myomiR-BAF60 variant network" regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) miR-1.2, miR-133 and miR-206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. miRNA modulation upon Histone Deacetylase inhibition in Fibro-Adipogenic Progenitors (FAPs) derived from young mdx mice was evaluated by small RNA-sequencing in 2 controls and 2 treated samples

Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration M-bM-^@M-^S is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an M-bM-^@M-^\HDAC-myomiR-BAF60 variant networkM-bM-^@M-^] regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a M-bM-^@M-^\latentM-bM-^@M-^] myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) 1.2, 133 and 206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. Genome-wide chromatin accessibility patterns in FAPs cells derived from mdx mice at different ages treated either with HDAC inhibitor Trichostatin A (TSA) or with vehicle (saline solution) were assessed using NA-seq (PMID: 19289091)

Project description:Fibro-Adipogenic Progenitors (FAPs) are currently defined by their anatomical position, expression of non-specific membrane-associated proteins, ability to adopt multiple lineages and to perform different biological activities in response to physiological or pathological stimuli. Gene expression analysis at single cell level revealed the intrinsic heterogeneity of FAPs and uncovered discrete subpopulations (subFAPs), which can be prospectively isolated by FACS, based on the expression levels of Tie2 and Vcam1. Tie2-expressing (Tie2+) and Tie2/Vcam1 double negative (DN) subFAPs were present in unperturbed muscles and promptly expanded upon acute injury. By contrast, Vcam1-expressing subFAPs (Vcam1+) were undetectable in unperturbed muscles, but appeared “de novo” upon acute injury and expanded with a shifted kinetic compared to Tie2+ and DN FAPs. While Vcam1+ subFAPs were completely cleared upon resolution of muscle regeneration following acute injury, they persisted in chronically injured muscles from the mdx mouse model of Duchenne Muscular Dystrophy (DMD). “Nested” RNA-seq analysis of subFAPs revealed subpopulation-specific gene expression profiles that were dynamically regulated along the regeneration process, predicted specific biological activities and functional interactions with other cell types, and exhibited DMD-specific signatures. In particular, Vcam1+ subFAPs showed enrichment in fibrotic gene expression and myofibroblast markers, and their altered clearance in acutely injured muscles upon macrophage depletion was associated with fibrosis. These data reveal the individual contribution of distinct subFAPs to the physiological and pathological repair of skeletal muscles, thereby providing new insights into the pathogenesis of muscular dystrophies and targets for selective therapeutic interventions. RNA-seq study of bulk FAPs or subFAPs isolated by Fluorescence Activated Cell Sorting (FACS) from hind limb muscles of young (3 months old) mice. RNA-seq was performed in cells from wild type mice, either unperturbed (WT) or at 3 days post notexin-mediated intramuscular acute injury (WT-inj 3d). We also included dystrophic mice (MDX), the murine model of Duchenne Muscular Dystrophy (DMD) that provides an experimental setting for chronic muscle injury

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HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibroadipogenic progenitors in dystrophic muscles

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