Facioscapulohumeral muscular dystrophy (FSHD) is a rare disease affecting 1;15,0000-20,000 individuals and is clinically characterized by progressive weakness and wasting of the facial and upper extremity muscles. In FSHD patients, due to the contraction of the D4Z4 macrosatellite repeat array on chromosome 4 (FSHD1), or due to SMCHD1 mutations (FSHD2), the somatic repression of the retrogene DUX4, which encodes the germline double homeobox 4 transcription factor, is incomplete leading to the variegated expression of the germline transcription factor in muscle fibers. SMCHD1 encodes a protein that regulates chromatin repression at different loci, and is necessary for the establishment and maintenance of the monoallelic expression of the protocadherin (PCDH) gene cluster on human chromosome 5. Preliminary studies show that PCDH gene cluster regulation is impaired in SMCHD1 mutation carriers. The objectives of this project are to (1) determine the exact role of SMCHD1 in the regulation of the PCDH gene cluster in neuronal and non-neuronal (muscle) cells, to (2) document the extend of PCDH gene cluster dysregulation in SMCHD1 mutation carriers and to (3) determine the functional consequence of PCDH gene cluster dysregulation in muscle cells. To accomplish these objectives I will combine quantitative chromosome immunoprecipitation followed by sequencing (ChIP- seq) and ChIP-PCR experiments to interrogate the regulation of the PCDH gene cluster in FSHD2 patient primary muscle cells and, as a reference, in neuronal SK-N-SH cells. This I will combine with functional genomics strategies (knock down and overexpression of critical regulators of the PCDH gene cluster) to dissect the function and hierarchy of these chromatin modifiers in PCDH gene cluster regulation, and functional studies of muscle cell differentiation to establish the role of PCDH gene cluster proteins in a non-neuronal context. The long term goal of these lines of investigation is to uncover the consequences of FSHD2 mutations on PCDH gene cluster regulation and to understand how these alterations in transcription are leading to FSHD phenotypes.

Public Health Relevance

The aim of my research is to understand the alterations to the epigenetic regulation of the PCDH gene cluster in muscle cells when SMCHD1 is mutated, the cause of FSHD2. This research will further define the clinical spectrum of FSHD2 patients, a group of patients that for many years has been overlooked by the scientific and clinical community in the absence of a clear diagnosis, providing a molecular and cellular basis of clinical observations. Additionally our findings will provide a rational basis for improved diagnosis and personalized treatment of FSHD2.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10B-B (20)L)
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Boyce, Amanda T
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Leiden University Medical Center
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2333 -ZA
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