This application is the natural extension of the parent grant, entitled ""Control of muscle gene expression by signaling pathways" (for which progress report is provided), and seeks to decipher the functional relationship between muscle-specific miRNAs and the formation of SWI/SNF sub-complexes containing mutually exclusive BAF60 variants that direct the myogenic or the fibro-adipogenic program in muscle-derived pluripotent cells. This miRNAs-SWI/SNF network is controlled by histone deacetylases - HDACs - and is influenced by extrinsic cues derived from the regeneration environment of dystrophic muscles. Thus, an important goal of this proposal is to determine the impact of signals generated by dystrophic muscles at different stages of disease progression on a novel regulatory axis - consisting of HDAC, miRNA and BAF60 variants - which constitutes the restriction point of the decision of muscle-derived pluripotent cells to adopt a myogenic or an adipogenic fate. As such, this proposal will shed light on an unanticipated intracellular network that links regeneration signals to the epigenetic control of muscular dystrophy pathogenesis, and will illustrate the mechanism underlying the beneficial effects of HDAC inhibitors in dystrophic muscles. We will use a combination of approaches, including genome-wide coding RNA and miRNA analysis, ChIP- based and proteomic approaches, to deconvolute the network of miRNA interactions with chromatin- associated complexes that shape the epigenome of muscle interstitial cells from dystrophic muscles. We will also perform experiments aimed at evaluating the functional interactions between muscle interstitial cells and satellite cells, and the regulation of these interactions in co-culture and in vivo upon cell transplantation, using different mouse models. These experiments will determine the impact of regeneration cues and HDAC blockade on interactions between muscle interstitial cells and satellite cells. Because muscle interstitial cells and satellite cells are candidate cellular determinants of compensatory regeneration or adipose infiltration and fibrosis in diseased muscles, the information gathered from this study will fill a critical gap of knowledge on the molecular basis of disease-associated changes in skeletal muscles. Likewise, this research might shed light on the interactions between different cell types within the "regeneration niche", and the contribution that disruption of these interactions has to the regeneration decline in aged muscles.
Specific aims are:
Aim 1 - Integration of Mass-spect/Microarray/ChIP analyses to decipher the HDAC-miRNA- SWI/SNF network in Sca1+ MICs;
Aim 2 - Modulation of lineage commitment of Sca1+ MICs by targeting miRNA/BAF60 networks in vitro;
Aim 3 - Modulation of lineage commitment of Sca1+ MICs by targeting miRNA/BAF60c network in vivo;
Aim 4 - Determine the contribution of regeneration-activated p38-BAF60c signaling to the activation of the myogenic potential of Sca1+ MICs

Public Health Relevance

This competitive renewal of the grant entitled Control of muscle gene expression by signaling pathways is the natural extension of the parent project and seeks to investigate the reciprocal interactions between myogenic miRNAs and chromatin remodeling SWI/SNF complexes, as a key regulatory axis at the restriction point of the decision of muscle-derived pluripotent cells to adopt a myogenic or an fibro-adipogenic fate.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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