AFM-21030 (DSB.AD007.149)
Thematic area
Project area
Biomedicina Traslazionale (DSB.AD007)Structure responsible for the research project
Istituto di Biochimica e Biologia Cellulare (IBBC)
Other structures collaborating in the research project
Project manager
FABIO MAMMANO
Phone number: 0690091307
Email: fabio.mammano@cnr.it
Abstract
The most common group of Lamin A/C-associated diseases are the muscular dystrophies such as Emery Dreifuss Muscular Dystrophy (EDMD). Although the penetrance of EDMD varies a lot among patients, suggesting an involvement of the individual epigenetic background to the disease is still unclear which is the epigenetic role of Lamin A/C in the aberrant muscle differentiation observed in EDMD. We propose a model of nuclear architecture depicting Lamin A/C as determinant of gene expression regulation throughout the interplay with specific epigenetic regulators. In our recent work we described a clear interplay between Lamin A/C and key epigenetic repressors, the Polycomb group (PcG) of proteins. We have shown that,at the onset myogenesis, a fine regulation of this crosstalk, by controlling the timing of muscle-specific gene activation, ensures a correct muscle differentiation. With this project we propose to describe how PcG repressors may contribute to the EDMD pathogenesis and progression.
Goals
The long-term goal of our research is the identification of therapeutically relevant early-stage epigenetic alterations in EDMD pathogenesis and the definition of their interplay in disease progression. This will be achieved using two mouse models of EDMD and innovative techniques, based on high-throughput DNA sequencing to fulfill the following aims: 1. Evaluating muscle regeneration in the EDMD H222P mouse model 2. Dissection of the functional contribution of PcG proteins and chromatin compartmentalization in EDMD pathology 3. Tissue-specific analysis of senescence programs in EDMD patients-derived cells. The novelty of our project is a new approach to EDMD research that will explore the epigenetic aspect of lamin function during different stages of dystrophy development, providing a full understanding of EDMD pathogenesis and progression as an evolving complex system. If successful this proposal will give a massive output to progress in elucidating relevance of epigenetic factors in regulating satellite stem cell niche, and the contribution of their dysfunctions, imposed by pathological conditions (Lmna mutation), to EDMD pathology. The identification of epigenetic defects that
Start date of activity
01/10/2017
Keywords
epigenetica, chromatin conformation, emery dreifuss muscular dystrophy
Last update: 16/06/2025