Myogenic Enhancers Regulate Expression of the Facioscapulohumeral Muscular Dystrophy-Associated DUX4 Gene
Authors
Himeda, Charis L.Debarnot, Celine
Homma, Sachiko
Beermann, Mary Lou
Miller, Jeffrey B.
Jones, Peter L.
Jones, Takako I.
UMass Chan Affiliations
Department of Cell and Developmental BiologyDocument Type
Journal ArticlePublication Date
2014-06-01Keywords
Facioscapulohumeral muscular dystrophyFSHD
Cell Biology
Developmental Biology
Molecular Biology
Molecular Genetics
Musculoskeletal Diseases
Nervous System Diseases
Metadata
Show full item recordAbstract
Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic dysregulation of the chromosome 4q35 D4Z4 macrosatellite. However, this does not account for the tissue specificity of FSHD pathology, which requires stable expression of an alternative full-length mRNA splice form of DUX4 (DUX4-fl) from the D4Z4 array in skeletal muscle. Here, we describe the identification of two enhancers, DUX4 myogenic enhancer 1 (DME1) and DME2 which activate DUX4-fl expression in skeletal myocytes but not fibroblasts. Analysis of the chromatin revealed histone modifications and RNA polymerase II occupancy consistent with DME1 and DME2 being functional enhancers. Chromosome conformation capture analysis confirmed association of DME1 and DME2 with the DUX4 promoter in vivo. The strong interaction between DME2 and the DUX4 promoter in both FSHD and unaffected primary myocytes was greatly reduced in fibroblasts, suggesting a muscle-specific interaction. Nucleosome occupancy and methylome sequencing analysis indicated that in most FSHD myocytes, both enhancers are associated with nucleosomes but have hypomethylated DNA, consistent with a permissive transcriptional state, sporadic occupancy, and the observed DUX4 expression in rare myonuclei. Our data support a model in which these myogenic enhancers associate with the DUX4 promoter in skeletal myocytes and activate transcription when epigenetically derepressed in FSHD, resulting in the pathological misexpression of DUX4-fl.Source
Himeda CL, Debarnot C, Homma S, Beermann ML, Miller JB, Jones PL, Jones TI. Myogenic Enhancers Regulate Expression of the Facioscapulohumeral Muscular Dystrophy-Associated DUX4 Gene. Mol Cell Biol. 2014 Jun;34(11):1942-55. doi:10.1128/MCB.00149-14. Link to article on publisher's websiteDOI
10.1128/MCB.00149-14Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43874PubMed ID
24636994Related Resources
Link to article in PubMedae974a485f413a2113503eed53cd6c53
10.1128/MCB.00149-14