Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD |
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Authors: | Judit Balog Peter E. Thijssen Jessica C. de Greef Bharati Shah Baziel G.M. van Engelen Kyoko Yokomori Stephen J. Tapscott Rabi Tawil Silvère M. van der Maarel |
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Affiliation: | 1.Department of Human Genetics; Leiden University Medical Center; Leiden, The Netherlands;2.Department of Neurology; University of Rochester Medical Center; Rochester, NY USA;3.Department of Neurology; Radboud University; Nijmegen Medical Center; Nijmegen, The Netherlands;4.Department of Biological Chemistry; School of Medicine; University of California; Irvine, CA USA;5.Division of Human Biology; Fred Hutchinson Cancer Research Center; Seattle, WA USA |
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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. |
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Keywords: | D4Z4 DUX4 FSHD Histone Modifications chromatin compaction score chromatin immunoprecipitation clinical severity score muscle pathology score |
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