To understand normal development and differentiation, it is necessary to determine the mechanisms by which cells initiate new programs of gene expression and promote 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 differentiation. We have made extensive use of cell culture models to identify and characterize chromatin remodeling enzyme function during skeletal muscle differentiation. Via modification of existing methodologies, we are now also capable of examining changes in chromatin structure and regulatory protein interactions that lead to gene activation during embryonic myogenesis and during the activation and maintenance of gene expression in adult tissue. Recent advances allow us to examine the regulation of myogenic gene expression specifically in the somites, at the start of myogenesis in the embryo, which further extends our abilities to understand the molecular control of myogenesis in the context of embryonic development. This renewal application will focus on SWI/SNF chromatin remodeling enzyme function at several levels. We will investigate how SWI/SNF enzymes cooperate with myogenic transcription factors and histone modifying enzymes to promote temporal control of myogenic gene expression (AIm 1). We will investigate how signal transduction pathways required for myogenesis regulate chromatin remodeling enzyme function (Aim 2). Finally, we will investigate SWI/SNF chromatin remodeling enzyme function in the differentiation dependent rearrangement of myogenic gene positioning in the nucleus and how this process contributes to the temporal control of myogenic gene expression (Aim 3).

Public Health Relevance

Our proposed studies addressing the regulation of tissue-specific gene expression during embryonic and adult skeletal muscle differentiation and maintenance at a molecular level 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 #
5R01GM056244-17
Application #
8691855
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Carter, Anthony D
Project Start
1997-08-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
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
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
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
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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