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.
|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|
|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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