PROJECT 2 r RNA Regulation in FSHD I We have demonstrated that multiple regions of D4Z4 are transcribed in the sense and antisense direction and are processed to small -21 nt fragments. We also have preliminary data demonstrating that RNA processing and possibly protein production might be developmentally regulated during the transition from ES cells to differentiated cells. This leads to the hypothesis that developmentally regulated transcription and RNA processing produces biologically functional RNA or proteins from the D4Z4 region, including but not limited to the full-length DUX4 protein, which contribute to the pathophysiology of FSHD. Therefore, the long-term goal is to identify the RNA, RNA fragments, and/or protein expressed from the D4Z4 region in FSHD that causes muscular dystrophy.
Aim 1 will characterize the biological function of the small RNA fragments produced from D4Z4 RNAs and determine whether small RNAs contribute to the pathophysiology of FSHD;
Aim 2 will test the hypothesis that the D4Z4 repeats regulate DUX4 expression and have a biological role in early embryonic development;
and Aim 3 will determine whether repressive chromatin can be re-established in the D4Z4 units on the disease-associated pathogenic allele, either in a deleted pathogenic allele or in a non-deleted """"""""phenotypic"""""""" FSHD2 allele.
The significance of these studies is that identifying the mechanisms establishing developmental epigenetic repression at D4Z4 and the role of the small RNAs produced from the D4Z4 region will provide a new basis for determining FSHD pathophysiology and validating new targets for interventional therapies.
|van den Boogaard, Marlinde L; Lemmers, Richard J F L; CamaÃ±o, 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|
|Jagannathan, Sujatha; Shadle, Sean C; Resnick, Rebecca et al. (2016) Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells. Hum Mol Genet :|
|van den Boogaard, Marlinde L; Lemmers, Richard J L F; Balog, Judit et al. (2016) Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy. Am J Hum Genet 98:1020-9|
|Tawil, Rabi; Padberg, George W; Shaw, Dennis W et al. (2016) Clinical trial preparedness in facioscapulohumeral muscular dystrophy: Clinical, tissue, and imaging outcome measures 29-30 May 2015, Rochester, New York. Neuromuscul Disord 26:181-6|
|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|
|Daxinger, Lucia; Tapscott, Stephen J; van der Maarel, SilvÃ¨re M (2015) Genetic and epigenetic contributors to FSHD. Curr Opin Genet Dev 33:56-61|
|Statland, Jeffrey M; Donlin-Smith, Colleen M; Tapscott, Stephen J et al. (2015) Milder phenotype in facioscapulohumeral dystrophy with 7-10 residual D4Z4 repeats. Neurology 85:2147-50|
|Lim, Jong-Won; Snider, Lauren; Yao, Zizhen et al. (2015) DICER/AGO-dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD. Hum Mol Genet 24:4817-28|
|Statland, Jeffrey M; Shah, Bharati; Henderson, Don et al. (2015) Muscle pathology grade for facioscapulohumeral muscular dystrophy biopsies. Muscle Nerve 52:521-6|
|Statland, Jeffrey M; Odrzywolski, Karen J; Shah, Bharati et al. (2015) Immunohistochemical Characterization of Facioscapulohumeral Muscular Dystrophy Muscle Biopsies. J Neuromuscul Dis 2:291-299|
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