Abstract

Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of the embryonic transcription factor DUX4 in skeletal muscle. A major mechanism of DUX4-induced cell toxicity in FSHD muscle is through the transcription of the HSATII pericentromeric repeats and their formation of single and double-stranded intranuclear ribonucleoprotein (RNP) complexes. In this proposal, we will determine the molecular components the RNP complexes and mechanisms of their cell toxicity. The significance of this proposal is that it will establish mechanisms of DUX4-induced pathology in FSHD muscle that will support future therapeutic interventions. The long-term goal of this project is to establish the mechanisms of DUX4-induced pathology in FSHD muscle. The overall hypothesis is that expression of DUX4 in FSHD muscle results in the accumulation of stable RNP complexes that alter the post-transcriptional regulation of other cellular RNAs and modulates the innate immune response pathways to inhibit the normal response to double-stranded RNAs.
The specific aims of the proposal are:
(Aim 1) Determine the RNAs and the proteins that comprise the intranuclear ribonucleoprotein complexes and their contribution to cell toxicity and genome instability.
(Aim 2) Determine whether DUX4 regulates the selective degradation or translation of specific subsets of mRNAs.
(Aim 3) Test the hypothesis that interactions between DUX4 and components of the innate immune response pathway represent a conserved function to modulate ISG induction by dsRNAs. Together, these aims will further establish the molecular basis of FSHD pathophysiology and identify new opportunities for future therapies.

Public Health Relevance

The proposed research will identify the molecular mechanisms of cellular toxicity and dysregulation induced by DUX4 through modulation of RNAs, double-stranded RNAs, and the innate immune response pathways induced by double-stranded RNAs. The health relevance of this research is that these mechanisms contribute to the pathophysiology of facioscapulohumeral muscular dystrophy and the proposed studies will provide the basis for future therapeutic development.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR045203-21
Application #
10140048
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Carifi, Emily Foran
Project Start
1998-09-01
Project End
2025-12-31
Budget Start
2021-01-15
Budget End
2021-12-31
Support Year
21
Fiscal Year
2021
Total Cost
Indirect Cost

  Institution

Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109

  Publications

Balog, Judit; Goossens, Remko; Lemmers, Richard J L F et al. (2018) Monosomy 18p is a risk factor for facioscapulohumeral dystrophy. J Med Genet 55:469-478
Campbell, Amy E; Shadle, Sean C; Jagannathan, Sujatha et al. (2018) NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins. Elife 7:
Campbell, Amy E; Belleville, Andrea E; Resnick, Rebecca et al. (2018) Facioscapulohumeral dystrophy: activating an early embryonic transcriptional program in human skeletal muscle. Hum Mol Genet 27:R153-R162
Hendrickson, Peter G; Doráis, Jessie A; Grow, Edward J et al. (2017) Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat Genet 49:925-934
Whiddon, Jennifer L; Langford, Ashlee T; Wong, Chao-Jen et al. (2017) Conservation and innovation in the DUX4-family gene network. Nat Genet 49:935-940
Campbell, Amy E; Oliva, Jonathan; Yates, Matthew P et al. (2017) BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. Skelet Muscle 7:16
Shadle, Sean C; Zhong, Jun Wen; Campbell, Amy E et al. (2017) DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy. PLoS Genet 13:e1006658
van den Boogaard, Marlinde L; Lemmers, Richard J F L; Camaño, Pilar et al. (2016) Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2. Eur J Hum Genet 24:78-85
Feng, Qing; Snider, Lauren; Jagannathan, Sujatha et al. (2015) A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. Elife 4:
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

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