title: Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD.
abstract: The aim of our study was to identify relationships between epigenetic parameters correlating with a relaxed chromatin state of the DUX4 promoter region and clinical severity as measured by a clinical severity score or muscle pathologic changes in D4Z4 contraction-dependent (FSHD1) and -independent (FSHD2) facioscapulohumeral muscular dystrophy patients. Twenty primary fibroblast (5 control, 10 FSHD1 and 5 FSHD2) and 26 primary myoblast (9 control, 12 FSHD1 and 5 FSHD2) cultures originating from patients with FSHD and controls were analyzed. Histone modification levels were determined by chromatin immunoprecipitation. We examined correlations between the chromatin compaction score (ChCS) defined by the H3K9me3:H3K4me2 ratio and an age corrected clinical severity score (CSS) or muscle pathology score (MPS). Possible relationships were investigated using linear regression analysis and significance was tested by Pearson's product-moment coefficient.       We found a significant difference of the ChCS between controls and patients with FSHD1 and between controls and patients with FSHD2. Tissue specific differences in ChCS were also observed. We also found a near-significant relationship between ChCS and the age corrected CSS in fibroblasts but not in myoblasts. Surprisingly, we found a strong correlation between the MPS of the vastus lateralis and the CSS. Our results confirm the D4Z4 chromatin relaxation previously shown to be associated with FSHD in a small number of samples. A possible relationship between clinical and epigenetic parameters could be established in patient fibroblasts, but not in myoblasts. The strong correlation between the MPS of the vastus lateralis and the CSS suggests that this muscle can be used to study for surrogate markers of overall disease severity.
authors.affiliation: Department of Human Genetics; Leiden University Medical Center; Leiden, The Netherlands.
authors.forename: Judit
authors.initials: J
authors.lastname: Balog
authors.forename: Peter E
authors.initials: PE
authors.lastname: Thijssen
authors.forename: Jessica C
authors.initials: JC
authors.lastname: de Greef
authors.forename: Bharati
authors.initials: B
authors.lastname: Shah
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yokomori
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012044:Regression Analysis; D012720:Severity of Illness Index
chemical_list: D002843:Chromatin; C121257:DUX4L1 protein, human; D006657:Histones; D018398:Homeodomain Proteins