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.
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