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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS069539-04
Application #
8434926
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$292,122
Indirect Cost
$129,903
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Zeng, Weihua; Chen, Yen-Yun; Newkirk, Daniel A et al. (2014) Genetic and epigenetic characteristics of FSHD-associated 4q and 10q D4Z4 that are distinct from non-4q/10q D4Z4 homologs. Hum Mutat 35:998-1010
Statland, Jeffrey; Tawil, Rabi (2014) Facioscapulohumeral muscular dystrophy. Neurol Clin 32:721-8, ix
Block, Gregory J; Narayanan, Divya; Amell, Amanda M et al. (2013) Wnt/*-catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells. Hum Mol Genet 22:4661-72
Krom, Yvonne D; Thijssen, Peter E; Young, Janet M et al. (2013) Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. PLoS Genet 9:e1003415
Sacconi, Sabrina; Lemmers, Richard J L F; Balog, Judit et al. (2013) The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet 93:744-51
Block, Gregory J; Petek, Lisa M; Narayanan, Divya et al. (2012) Asymmetric bidirectional transcription from the FSHD-causing D4Z4 array modulates DUX4 production. PLoS One 7:e35532
Balog, Judit; Miller, Dan; Sanchez-Curtailles, Elena et al. (2012) Epigenetic regulation of the X-chromosomal macrosatellite repeat encoding for the cancer/testis gene CT47. Eur J Hum Genet 20:185-91
Geng, Linda N; Yao, Zizhen; Snider, Lauren et al. (2012) DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell 22:38-51
Sacconi, Sabrina; Camano, Pilar; de Greef, Jessica C et al. (2012) Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity. J Med Genet 49:41-6

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