Abstract

PROJECT 1 The Genetic and Epigenetic Basis for FSIHD We have demonstrated that FSHD is caused by a contraction-cfepencfenf (FSHD1) or contractionindependent (FSHD2) change in chromatin structure of D4Z4 only when this contraction occurs on a specific genetic background (4qA161). This leads to the hypothesis that a change in D4Z4 chromatin structure on the 4qA161 haplotype is essential for FSHD pathology. Therefore, the long-term goal is to identify the specific DNA sequences and the epigenetic modifications that together confer pathogenicity to 4qA161.
Aim 1 will identify and functionally characterize the disease haplotype-specific sequence variants of the distal repeat unit and flanking pLAM sequence. Recent studies identified this part of the FSHD locus as the minimal essential region;
Aim 2 will identify and functionally characterize the chromatin structure of this minimal essential region test the hypothesis that the D4Z4 repeats regulate DUX4 expression and have a biological role in early embryonic development;
and Aim 3 will determine the genetic and epigenetic characteristics of D4Z4 in human ES cells to establish the developmental role of D4Z4 in relation to the clinical features of FSHD.

Public Health Relevance

The significance of these studies is that identifying the genetic and epigenetic conditions required for FSHD will provide fundamental insight into the pathophysiology of FSHD as well as providing new avenues for interventional therapies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS069539-05
Application #
8634145
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

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

  Publications

Lemmers, Richard J L F; van der Vliet, Patrick J; Vreijling, Jeroen P et al. (2018) Cis D4Z4 repeat duplications associated with facioscapulohumeral muscular dystrophy type 2. Hum Mol Genet 27:3488-3497
Lim, Jong-Won; Wong, Chao-Jen; Yao, Zizhen et al. (2018) Small noncoding RNAs in FSHD2 muscle cells reveal both DUX4- and SMCHD1-specific signatures. Hum Mol Genet :
Lemmers, Richard Jlf; van der Vliet, Patrick J; Balog, Judit et al. (2018) Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2. Eur J Hum Genet 26:94-106
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:
de Greef, Jessica C; Krom, Yvonne D; den Hamer, Bianca et al. (2018) Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model. Hum Mol Genet 27:716-731
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
Mul, Karlien; Heatwole, Chad; Eichinger, Katy et al. (2018) Electrical impedance myography in facioscapulohumeral muscular dystrophy: A 1-year follow-up study. Muscle Nerve 58:213-218
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
Mason, Amanda G; Slieker, Roderick C; Balog, Judit et al. (2017) SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes. Skelet Muscle 7:12

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