title: Loss of epigenetic silencing of the DUX4 transcription factor gene in facioscapulohumeral muscular dystrophy.
abstract: Current genetic and molecular evidence best supports an epigenetic mechanism for facioscapulohumeral muscular dystrophy (FSHD), whereby de-repression of the D4Z4 macrosatellite array leads to aberrant expression of the DUX4 transcription factor in skeletal muscle. This de-repression is triggered by either array contraction or (more rarely) by mutation of the SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) gene. Activation of DUX4 targets, including germline genes and several mammalian retrotransposons, then drives pathogenesis. A direct role for DUX4 mRNA in suppression of nonsense-mediated decay pathways has recently been demonstrated and may also contribute to muscle pathology. Loss of D4Z4 repression in FSHD is observed as hypomethylation of the array accompanied by loss of repressive chromatin marks. The molecular mechanisms of D4Z4 repression are poorly understood, but recent data have identified an Argonaute (AGO)-dependent siRNA pathway. Targeting this pathway by exogenous siRNAs could be a therapeutic strategy for FSHD.
authors.affiliation: School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK jane.hewitt@nottingham.ac.uk.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Hewitt
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D044127:Epigenesis, Genetic; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C115848:AGO1 protein, human; D060565:Argonaute Proteins; D002868:Chromosomal Proteins, Non-Histone; C121257:DUX4L1 protein, human; D039642:Eukaryotic Initiation Factors; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; C578241:SMCHD1 protein, human; D014157:Transcription Factors