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.
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.
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|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|
|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|
|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|
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