The overall aim of this proposal is to fill the gap of knowledge on how intra-cellular signaling pathways convert environmental cues into chromatin modifications to regulate gene expression during muscle differentiation. The elucidation of the molecular basis by which the information transmitted by signaling cascades is deciphered by chromatin-binding proteins and broadcasted to other components of the transcription machinery will reveal new targets for selective pharmacological interventions aimed at modulating gene expression to influence muscle growth and regeneration in normal and pathological conditions.
In specific aim 1, we will investigate how the chromatin remodeling SWI-SNF complex discriminates between the information transmitted by the differentiation-activated p38 signaling vs stress- or inflammation- activated p38 and JNK cascades. We will test the hypothesis that distinct phosphorylation patterns of the structural sub-units of the SWI/SNF complex - the BAFproteins - bydifferentiation- vs stress/inflammation- activated pathways establish the code that regulates SWI/SNF recruitment to the chromatin of muscle genes.
In specific aim 2, we will elucidate the molecular basis of acetyltransferase recruitment to the chromatin of muscle-gene regulatory elements in response to the pro-myogenic signaling elicited by IGF-1. We will test the hypothesis that AKT-mediated phosphorylation of specific residues located within the C/H3 region of the acetyltransferase p300, promotes the interaction with the muscle regulatory factor MyoD.
In specific aim 3, we will investigate whether the recruitment of SWI/SNF to the promoters of proliferation genes, which are silenced during differentiation, is also directed by the p38 pathway. We will also study the mechanism by which the cytostatic activity of differentiation-activated p38 converts the IGF1-activated pathway from a mitogenic to a pro-myogenic signaling. We will take advantage from information and reagents generated in specific aims 1 and 2 to study the functional interdependence between the p38 pathway and the PiSK/AKT signaling at the chromatin level. This study will improve our knowledge on the molecular mechanism by which sjgnal transduction pathways regulate gene expression during muscle formation, growth and regeneration. The results gathered from this proposal will have an impact on regenerative medicine, as they will eventually reveal new targets for pharmacological strategies to selectively modulate gene expression in the therapy of neuromuscular disorders and other pathological conditions accompanied by muscle loss, such as cancer-associated cachexia and aging-associated sarcopenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052779-05
Application #
7761687
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2006-04-20
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$356,270
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Latella, Lucia; Dall'Agnese, Alessandra; Boscolo, Francesca Sesillo et al. (2017) DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation. Genes Dev 31:648-659
Malecova, Barbora; Dall'Agnese, Alessandra; Madaro, Luca et al. (2016) TBP/TFIID-dependent activation of MyoD target genes in skeletal muscle cells. Elife 5:
Toto, Paula Coutinho; Puri, Pier Lorenzo; Albini, Sonia (2016) SWI/SNF-directed stem cell lineage specification: dynamic composition regulates specific stages of skeletal myogenesis. Cell Mol Life Sci 73:3887-96
Sacco, Alessandra; Puri, Pier Lorenzo (2015) Regulation of Muscle Satellite Cell Function in Tissue Homeostasis and Aging. Cell Stem Cell 16:585-7
Albini, Sonia; Coutinho Toto, Paula; Dall'Agnese, Alessandra et al. (2015) Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis. EMBO Rep 16:1037-50
Farup, J; Madaro, L; Puri, P L et al. (2015) Interactions between muscle stem cells, mesenchymal-derived cells and immune cells in muscle homeostasis, regeneration and disease. Cell Death Dis 6:e1830

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