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 #
5P01NS069539-03
Application #
8376792
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$308,543
Indirect Cost
$135,953
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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
Jagannathan, Sujatha; Bradley, Robert K (2017) Congenital myotonic dystrophy-an RNA-mediated disease across a developmental continuum. Genes Dev 31:1067-1068
Feng, Qing; Jagannathan, Sujatha; Bradley, Robert K (2017) The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity. Mol Cell 67:239-251.e6
Lemmers, Richard Jlf; van der Vliet, Patrick J; Balog, Judit et al. (2017) Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2. Eur J Hum Genet :
Shadle, Sean C; Zhong, Jun Wen; Campbell, Amy E et al. (2017) DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy. PLoS Genet 13:e1006658
Mason, Amanda G; Slieker, Roderick C; Balog, Judit et al. (2017) SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes. Skelet Muscle 7:12
van den Boogaard, Marlinde L; Lemmers, Richard J F L; Camaño, 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
Mul, Karlien; van den Boogaard, Marlinde L; van der Maarel, Silvère M et al. (2016) Integrating clinical and genetic observations in facioscapulohumeral muscular dystrophy. Curr Opin Neurol 29:606-13
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

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