To understand normal development and differentiation, it is necessary to determine the mechanisms by which cells initiate new programs of gene expression and promote the formation of specific cell lineages. Typically, this involves activation of genes that are transcriptionally silent and that are likely incorporated into repressive chromatin structure. Evidence supports the idea that differentiation-specific transcriptional regulators and enzymes that remodel or alter chromatin structure cooperate to render genomic DNA more accessible to the transcriptional machinery. The mammalian SWI/SNF (mSWI/SNF) enzyme family members remodel nucleosome structure in an ATP dependent manner and facilitate transcription factor function in vitro and in vivo. Components of these enzymes are essential for embryonic development and some can act as tumor suppressors or tumor promoters. Additionally, SWI/SNF enzymes are implicated in cell cycle control. Thus these enzymes are broadly required for normal cell function and for differentiation and development, and their misregulation is implicated in tumor formation. Skeletal muscle differentiation has long been a model for studying fundamental principles of tissue-specific gene expression and differentiation. The SWI/SNF chromatin remodeling enzymes play essential roles in these processes. This project will focus on the mechanisms by which different kinases and phosphatases involved in signaling pathways regulate the phosphorylation and function of SWI/SNF chromatin remodeling enzyme subunits in proliferating and differentiating myoblasts. We will employ methods to manipulate the expression of specific kinases, phosphatases and remodeling enzyme subunits and will manipulate function through use of inhibitors and mutagenensis. We will analyaze the effects of such approaches on gene expression, chromatin binding and remodeling, transcription factor function, local higher-order gene structure, and overall genome organization. The work will provide new paradigms for understanding how signaling molecules converge on chromatin to regulate tissue differentiation and development.

Public Health Relevance

Our proposed studies address how sigaling molecules converge on chromatin to regulate chromatin remodeling, tissue-specific gene expression and tissue differentiation. Using skeletal muscle differentiation as a model, our work will provide molecular mechanisms defining how signaling pathways modify a specific chromatin remodeling enzyme to mediate embryonic and adult skeletal muscle differentiation and maintenance. The work will have significant impact on our overall understanding of muscle development in the embryo and muscle regeneration in the adult. This work will also increase our understanding of changes that occur in muscle diseases where increased muscle growth (hypertrophy) or reduced muscle development (hypotrophy) are exhibited and on the formation of rhabdomyosarcomas, which are tumors of myogenic derivation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM136393-01
Application #
9932021
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Carter, Anthony D
Project Start
2020-04-01
Project End
2025-02-28
Budget Start
2020-04-01
Budget End
2021-02-28
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655