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Epigenetic regulation in facioscapulohumeral muscular dystrophy type 2 (FSHD2)

Award Number: F32AR067050
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/22/2014
PERIOD OF PERFORMANCE END DATE: 09/21/2017

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Epigenetic regulation in facioscapulohumeral muscular dystrophy type 2 (FSHD2) - DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2016 ( Subtotal = $8,850 )
2016	2016	ACADEMISCH ZIEKENHUIS LEIDEN	LEIDEN UNIVERSITY MEDICAL CTR	LEIDEN 2333ZA				NLD	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	9/15/2016	NON-COMPETING CONTINUATION	$7,850
2016	2016	ACADEMISCH ZIEKENHUIS LEIDEN	LEIDEN UNIVERSITY MEDICAL CTR	LEIDEN 2333ZA				NLD	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	9/16/2016	NON-COMPETING CONTINUATION	$1,000
														Subtotal = $8,850

Issue Date FY: 2014 ( Subtotal = $7,850 )
2014	2014	ACADEMISCH ZIEKENHUIS LEIDEN	LEIDEN UNIVERSITY MEDICAL CTR	LEIDEN 2333ZA				NLD	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/22/2014	NEW	$7,850
														Subtotal = $7,850

Grand Total All Awards = $16,700

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Epigenetic regulation in facioscapulohumeral muscular dystrophy type 2 (FSHD2)

Award Number: F32AR067050

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/22/2014

PERIOD OF PERFORMANCE END DATE: 09/21/2017

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