The aim of this research program is to characterize at the biochemical and molecular level, transcription factors and chromatin remodeling proteins regulating skeletal muscle specification and development. Thus, the interplay between non-coding RNAs such as miRNAs, enhancers-RNAs and lncRNAs with chromatin organization and genome topology in myogenesis, is of our utmost interest.

Skeletal muscles constitute about 40% of its total body mass. Most skeletal muscles are composed of a mixture of myofibers with distinct contractile, metabolic, resistance to fatigue properties, as well as differential vulnerability in pathophysiological conditions. Oxidative myofibers are more fatigue resistant and have higher mitochondrial content, to facilitate β-oxidation. Fast glycolytic myofibers fatigue more easily and rely on glycolysis for energy production.

Although fiber types are established shortly after birth, adult skeletal muscle retains remarkable plasticity in order to adapt to changing demands. However, certain pathological conditions, such as muscular dystrophy, result in a shift to more oxidative/slow fibers, in part because fast fibers are more susceptible to damage. In addition, skeletal muscle is one of the organs most affected by aging, with estimated yearly losses of ~1% muscle mass and 3% muscle strength in the elderly, resulting in an accumulated net loss of >30% muscle mass during aging.

By understanding the molecular, cellular and epigenetic mechanisms mediating fiber type identity, our aim is to identify molecular targets to therapeutically induce specific muscle fibers to ameliorate diseases affecting muscle function.

This research program includes the identification of new drugs targeting key molecular regulators with the potential to promote muscle differentiation and regeneration. Through molecular docking and molecular dynamics, our aim is to establish a solid pipeline to discover and characterize novel therapeutic drugs for tissue regeneration.

Spinocerebellar ataxia type 7 (SCA7), is a neurodegenerative autosomal dominantly inherited disease caused by a CAG expansion in the coding region of the ATXN7 gene. By altering cerebellum and retina, SCA7 is characterized by gait ataxia, dysarthria, spasticity, retinal degeneration, and blindness.

To date, there is no cure for SCA7, therefore, a better knowledge of the molecular mechanisms lying the disease is crucial to advance into the effective therapy strategies. Ataxin-7, the encoded product of the ATXN7 gene, is part of a chromatin remodeling and transcriptional coactivator complex, however, with the expansion, the mutant protein tends to form nuclear inclusions altering transcriptional regulation and cellular pathways causing neurodegeneration.

Experimental evidence suggests a role for the mutant mRNA of ATXN7 as a toxic agent by the formation of nuclear aggregates; in addition, it has been suggested a chromatin reorganization as a consequence of CAG expansion with impact on gene expression.

In this research program, we use in vitro cell models for SCA7. By applying cutting-edge methodology based on the use of the CRISPR/dCas13a system and promoter capture Hi-C (PCHi-C) technology, our aim is to uncover new factors implicated in SCA7 and to dissect how higher-order chromatin organization contributes with altered gene expression patterns in SCA7.