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

Valentina Saccone, Silvia Consalvi, Lorenzo Giordani, Chiara Mozzetta, Iros Barozzi, Martina Sandoná, Tammy Ryan, Agustin Rojas-Muñoz, Luca Madaro, Pasquale Fasanaro, Giovanna Borsellino, Marco De Bardi, Gianmaria Frigè, Alberto Termanini, Xin Sun, Janet Rossant, Benoit G. Bruneau, Mark Mercola, Saverio Minucci, Pier Lorenzo Puri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)841-857
Number of pages17
JournalGenes and Development
Volume28
Issue number8
DOIs
Publication statusPublished - Apr 15 2014

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Keywords

  • BAF60
  • FAPs
  • HDAC
  • MicroRNA
  • Muscular dystrophy
  • SWI/SNF chromatin remodeling

ASJC Scopus subject areas

  • Developmental Biology
  • Genetics

Cite this

Saccone, V., Consalvi, S., Giordani, L., Mozzetta, C., Barozzi, I., Sandoná, M., Ryan, T., Rojas-Muñoz, A., Madaro, L., Fasanaro, P., Borsellino, G., De Bardi, M., Frigè, G., Termanini, A., Sun, X., Rossant, J., Bruneau, B. G., Mercola, M., Minucci, S., & Puri, P. L. (2014). HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles. Genes and Development, 28(8), 841-857. https://doi.org/10.1101/gad.234468.113