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. SWI/SNF enzymes 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 act as tumor suppressors. Additionally, SWI/SNF enzymes interact with other known tumor suppressors and 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. Modulation of kinase and phosphatase activities and mutation of modified amino acids in targeted subunit proteins will be the primary approaches to determining mechanisms by which phosphorylation of SWI/SNF enzyme subunits control gene expression and differentiation. 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
Research Project (R01)
Project #
5R01GM056244-21
Application #
9624769
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
1997-08-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
21
Fiscal Year
2019
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
Padilla-Benavides, Teresita; Nasipak, Brian T; Paskavitz, Amanda L et al. (2017) Casein kinase 2-mediated phosphorylation of Brahma-related gene 1 controls myoblast proliferation and contributes to SWI/SNF complex composition. J Biol Chem 292:18592-18607
Harada, Akihito; Ohkawa, Yasuyuki; Imbalzano, Anthony N (2017) Temporal regulation of chromatin during myoblast differentiation. Semin Cell Dev Biol 72:77-86
LeBlanc, Scott E; Wu, Qiong; Lamba, Pallavi et al. (2016) Promoter-enhancer looping at the PPAR?2 locus during adipogenic differentiation requires the Prmt5 methyltransferase. Nucleic Acids Res 44:5133-47
Hu, Yu-Jie; Imbalzano, Anthony N (2016) Global gene expression profiling of JMJD6- and JMJD4-depleted mouse NIH3T3 fibroblasts. Sci Data 3:160022
Gerstenberger, Brian S; Trzupek, John D; Tallant, Cynthia et al. (2016) Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit. J Med Chem 59:4800-11
Hu, Yu-Jie; Belaghzal, Houda; Hsiao, Wen-Yu et al. (2015) Transcriptional and post-transcriptional control of adipocyte differentiation by Jumonji domain-containing protein 6. Nucleic Acids Res 43:7790-804
Padilla-Benavides, Teresita; Nasipak, Brian T; Imbalzano, Anthony N (2015) Brg1 Controls the Expression of Pax7 to Promote Viability and Proliferation of Mouse Primary Myoblasts. J Cell Physiol 230:2990-7
Nasipak, Brian T; Padilla-Benavides, Teresita; Green, Karin M et al. (2015) Opposing calcium-dependent signalling pathways control skeletal muscle differentiation by regulating a chromatin remodelling enzyme. Nat Commun 6:7441
Harada, Akihito; Mallappa, Chandrashekara; Okada, Seiji et al. (2015) Spatial re-organization of myogenic regulatory sequences temporally controls gene expression. Nucleic Acids Res 43:2008-21
Cho, Ok Hyun; Mallappa, Chandrashekara; Hernández-Hernández, J Manuel et al. (2015) Contrasting roles for MyoD in organizing myogenic promoter structures during embryonic skeletal muscle development. Dev Dyn 244:43-55

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