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Figure 10 | Clinical Epigenetics

Figure 10

From: Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy

Figure 10

FSHD1-affected, FSHD1-nonmanifesting, FSHD2, and healthy subjects are characterized by distinct states of epigenetic susceptibility to DUX4-fl expression. Model for the different epigenetic states that distinguish healthy vs. FSHD1-affected vs. nonmanifesting vs. FSHD2 subjects. Healthy, unaffected subjects are characterized by stable repression of the distal pathogenic D4Z4 repeat, as indicated by DNA hypermethylation and chromatin compaction. Cells from these subjects express very low or undetectable levels of DUX4-fl, and are refractory to epigenetic induction of DUX4-fl. Cells from FSHD1-affected subjects display de-repression at the distal pathogenic D4Z4, as indicated by DNA hypomethylation and loss of chromatin compaction. These cells express detectable DUX4-fl, which is further induced upon treatment with epigenetic drugs. Cells from FSHD1-nonmanifesting subjects display an intermediate level of repression at the distal pathogenic D4Z4, as indicated by levels of DNA methylation and DUX4-fl inducibility which fall between those of FSHD1-affected and healthy, unaffected subjects. Despite lacking a contracted D4Z4 allele, cells from FSHD2 subjects are distinguished by severe hypomethylation at D4Z4 arrays, indicating a pronounced de-repression in these regions, which results in detectable expression of DUX4-fl. Interestingly, the shortest permissive 4q array in FSHD2 subjects tends to be shorter (approximately 16 RU) on average than the shortest 4q array in the healthy population (approximately 24 RU) [18,25]. *In genetically FSHD1 subjects, only the contracted 4q D4Z4 is hypomethylated; **In FSHD2 subjects, both 4q and 10q D4Z4 arrays are hypomethylated. Refer to text for more details.

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