Journal
BIOLOGY OPEN
Volume 7, Issue 4, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/bio.033977
Keywords
DUX4; Facioscapulohumeral dystrophy; Homeodomains; Muscular dystrophy; Skeletal muscle; Transactivation domain
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Funding
- Japan Society for the Promotion of Science [KAKENHI] [15K19477]
- National Institutes of Health (NIH) [R01AR060328, R01AR062587]
- Muscular Dystrophy Association [216422]
- Association Francaise contre les Myopathies [18248]
- FSH Society [FSHS-82016-2]
- Undergraduate Research Opportunities Program at Boston University
- Boston University Clinical and Translational Science Institute - National Center for Advancing Translational Sciences at the NIH [1UL1TR001430]
- Grants-in-Aid for Scientific Research [15K19477] Funding Source: KAKEN
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Aberrant expression of the full-length isoform of DUX4 (DUX4-FL) appears to underlie pathogenesis in facioscapulohumeral muscular dystrophy (FSHD). DUX4-FL is a transcription factor and ectopic expression of DUX4-FL is toxic to most cells. Previous studies showed that DUX4-FL-induced pathology requires intact homeodomains and that transcriptional activation required the C-terminal region. In this study, we further examined the functional domains of DUX4 by generating mutant, deletion, and fusion variants of DUX4. We compared each construct to DUX4-FL for (i) activation of a DUX4 promoter reporter, (ii) expression of the DUX4-FL target gene ZSCAN4, (iii) effect on cell viability, (iv) activation of endogenous caspases, and (v) level of protein ubiquitination. Each construct produced a similarly sized effect (or lack of effect) in each assay. Thus, the ability to activate transcription determined the extent of change in multiple molecular and cellular properties that may be relevant to FSHD pathology. Transcriptional activity was mediated by the C-terminal 80 amino acids of DUX4-FL, with most activity located in the C-terminal 20 amino acids. We also found that non-toxic constructs with both homeodomains intact could act as inhibitors of DUX4-FL transcriptional activation, likely due to competition for promoter sites.
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