Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 repeat that results in expression of the DUX4 retrogene. Mutations in SMCHD1 result in decreased D4Z4 epigenetic repression through its direct repressor activity at the D4Z4 repeat and cause FSHD. The broad and long-term goal of this application is to develop therapies for FSHD based on increasing SMCHD1 activity or protein level, or decreasing the activity of factor(s) that counter-act SMCHD1 epigenetic activity at the D4Z4 repeats. The specific goal of the research design is to determine the positive and negative modulators of SMCHD1 activity and their epistatic relationship to the epigenetic repression of the D4Z4 macrosatellite repeat and DUX4 expression.
Aim 1 will identify the molecular components and the biological functions of the pathways that regulate the post-transcriptional and post-translational production and activity of SMCHD1, and provide a rational basis for the therapeutic modulation of SMCHD1 in FSHD muscle.
Aim 2 will test the hypothesis that FSHD2-associated SMCHD1 variants partially inhibit the activity or stability of the wild-type protein and provide a rationale to target the variant isoforms as a therapeutic approach.
Aim 3 Identifies components of the SMCHD1 repressive complex and determines their role in D4Z4 epigenetic repression. Together, these studies will provide the basis for future therapeutic development based on increasing the epigenetic repression of D4Z4 in FSHD individuals.

Public Health Relevance

The proposed research will identify the fundamental molecular mechanisms that epigenetically repress the D4Z4 region through the production, modification, stability and interacting partners of SMCHD1. The health relevance of this research is that the failure of these mechanisms results in facioscapulohumeral muscular dystrophy and the proposed studies will provide the basis for future therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR066248-01
Application #
8687333
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2014-04-25
Project End
2019-03-31
Budget Start
2014-04-25
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Knopp, Paul; Krom, Yvonne D; Banerji, Christopher R S et al. (2016) DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis. J Cell Sci 129:3816-3831
Balog, Judit; Thijssen, Peter E; Shadle, Sean et al. (2015) Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics 10:1133-42
Daxinger, Lucia; Tapscott, Stephen J; van der Maarel, Silvère M (2015) Genetic and epigenetic contributors to FSHD. Curr Opin Genet Dev 33:56-61
Lemmers, Richard J L F; van den Boogaard, Marlinde L; van der Vliet, Patrick J et al. (2015) Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome. Hum Mutat 36:679-83
Lemmers, Richard J L F; Goeman, Jelle J; van der Vliet, Patrick J et al. (2015) Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum Mol Genet 24:659-69
Lemmers, Richard J L F; Tawil, Rabi; Petek, Lisa M et al. (2012) Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 44:1370-4