E-GEOD-51933 - Small RNA-sequencing of Fibro-Adipogenic Progenitors (FAPs) upon Histone Deacetylase inhibition in young mdx mice

Status
Released on 23 April 2014, last updated on 29 May 2014
Organism
Mus musculus
Samples (4)
Protocols (3)
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
Experiment type
RNA-seq of non coding RNA 
Contacts
Pier Lorenzo Puri <pl.puri@hsantalucia.it>, Luca Madaro, Pasquale Fasanaro, Pier L Puri, Silvia Consalvi, Valentina Saccone
Citation
HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles. Saccone V, Consalvi S, Giordani L, Mozzetta C, Barozzi I, Sandon� M, Ryan T, Rojas-Mu�oz A, Madaro L, Fasanaro P, Borsellino G, De Bardi M, Frig� G, Termanini A, Sun X, Rossant J, Bruneau BG, Mercola M, Minucci S, Puri PL. , Europe PMC 24682306
MINSEQE
Exp. designProtocolsVariablesProcessedSeq. reads
Files
Investigation descriptionE-GEOD-51933.idf.txt
Sample and data relationshipE-GEOD-51933.sdrf.txt
Additional data (1)E-GEOD-51933.additional.1.zip
Links