Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive muscular dystrophy affecting approximately 1/20,000 individuals. Although the disease is caused by a deletion of repeated sequence on chromosome 4, which is thought to inappropriately activate nearby genes, the identity of the key causative gene is unknown and mechanisms relating genes in the area to muscle pathology are unknown. There is currently no effective treatment for FSHD. We have screened candidate genes from the FSHD region of chromosome 4 in a cell culture system, and identified a gene (the double-homeodomain transcription factor, DUX4, which is embedded within the D4Z4 repeats on chromosome 4) with extreme toxicity to myoblasts. Using an inducible gene expression system, we show that expression of DUX4 causes changes in expression of a set of genes previously identified in microarray and proteomic studies as specifically misregulated in FHSD, including elements of stress response pathways, and the transcription factor MyoD. We further show that these responses involve competition with Pax7, a transcription factor at the apex of the myogenic hierarchy with a highly related homeodomain. We propose to investigate the molecular pathways downstream of DUX4 and identify genes relevant to muscle regeneration that are oppositely regulated by DUX4 and Pax7 (Aim 1), to generate novel cell and mouse models for FSHD based on expression of patient-derived D4Z4/DUX4 sequences (Aim 2), and to test the hypothesis that the stem or progenitor cell compartments of muscle are specifically affected by DUX4 in FSHD (Aim 3).

Public Health Relevance

Facioscapulohumeral muscular dystrophy (FSHD) a genetically dominant progressive muscular dystrophy associated with a deletion of repetitive sequences on chromosome 4. This deletion is thought to deregulate nearby genes and we have shown that one of the genes associated with this deletion, DUX4, causes myoblasts to become sensitive to oxidative stress, and interferes with myogenic pathways by competing with the muscle stem cell master regulator, Pax7. We propose to investigate the molecular pathways downstream of DUX4 and identify genes relevant to muscle regeneration that are oppositely regulated by DUX4 and Pax7 (Aim 1), to generate a mouse model for FSHD based on expression of patient-derived D4Z4/DUX4 sequences (Aim 2), and to test the hypothesis that the stem or progenitor cell compartments of muscle are specifically affected by DUX4 in FSHD (Aim 3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055685-04
Application #
8447055
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2010-03-19
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$398,093
Indirect Cost
$134,455
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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