Data Entry Maintenance

Metadata Commons Identifier

HMC000058

Project Title

Epigenomic Dynamics of Facioscapulohumeral Muscular Dystrophy (FSHD)

Project Description

Facioscapulohumeral muscular dystrophy (FSHD) is a multifaceted genetic disorder characterized by the gradual onset of muscle weakness and atrophy throughout a patient's lifetime. FSHD presents in two distinct types, FSHD type 1 (FSHD1) and FSHD type 2 (FSHD2), characterized by different epigenetic mechanisms. In FSHD1, the most common form affecting 95% of patients, DUX4 gene de-repression occurs due to partial deletion of the D4Z4 repeat, leading to reduced DNA methylation and repressive histone modifications on one 4qA allele, resulting in chromatin relaxation and DUX4 transcription in skeletal muscle. In contrast, FSHD2, accounting for the remaining 5% of cases, is caused by mutations in chromatin repressor genes, such as SMCHD1 (in >85% of FSHD2 cases) or DNMT3B, rather than D4Z4 repeat contractions. These mutations disrupt D4Z4 repression and allow for aberrant DUX4 expression. While there is agreement that DUX4 misexpression drives pathology in FSHD1 and FSHD2, it is unclear since DUX4 protein is undetectable in most FSHD patients. This leads to the question of how does a transiently expressed protein leads to chronic effects, even in its absence. Here, we hypothesize that transient expression of DUX4 induces persistent epigenetic changes encoded through chemical modifications to chromatin, permanently affecting the transcriptome of FSHD muscle cells to cause pathology. To test our hypothesis, we will analyze the epigenome using engineered patient-derived cell models following DUX4 expression. We will focus on two cell lineages affected in FSHD: <ul> <li>Myogenic cells, the main cellular target</li> <li>Fibro-Adipogenic Progenitors (FAPs), responsible for the fibrofatty infiltration that is invariably found in FSHD muscle.</li> </ul> In total, there are 2 FSHD patients, 1 engineered cell line has been derived from each patient, two clones have been generated for each cell line (healthy clone of myogenic cells and FSHD1 clone of FAPs) (cell lines have been provided by the lab of Professor Peter Zammit, King's College London -  https://www.kcl.ac.uk/research/the-zammit-group)

Project Funder(s)

SOLVE-FSHD

Project Institution(s)

University of British Columbia

Project Investigator(s)

Martin Hirst

Data Access Request URL*

Keywords

FSHD, muscle disorder, epigenomics

Publication Link

Study Completed

Cohort Name

FSHD patient-derived engineered cell models

Cohort Size

Disease/Condition Studied

facioscapulohumeral muscular dystrophy

Enrollment Time Window

Biobanking Consent Available

Medical History Available

Ethnicity Availability

Time Course

Patient Phenotypes

Patient Outcomes

Clinical Data Types Available

Time Course Data Points

Enrollment City

Groups

Project

Cohort

Enrollment City

Groups

Samples and Omics