DUX4 Activates Germline Genes, Retroelements, and Immune Mediators: Implications for Facioscapulohumeral Dystrophy

• Published in: Developmental cell 2012-01, Vol.22 (1), p.38-51
• Main Authors: Geng, Linda N., Yao, Zizhen, Snider, Lauren, Fong, Abraham P., Cech, Jennifer N., Young, Janet M., van der Maarel, Silvere M., Ruzzo, Walter L., Gentleman, Robert C., Tawil, Rabi, Tapscott, Stephen J.
• Format: Article
• Language: English
• Subjects: Animal models; Apoptosis; beta-Defensins - genetics; beta-Defensins - metabolism; Biological and medical sciences; biomarkers; Biomarkers - metabolism; Blotting, Western; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell Proliferation; Cells, Cultured; Chromatin Immunoprecipitation; Defensins; Differentiation; Dystrophy; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation; Germ Cells; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Immune response; Immunoenzyme Techniques; Infection; Luciferases - metabolism; Molecular and cellular biology; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Muscular dystrophy; Muscular Dystrophy, Facioscapulohumeral - genetics; Muscular Dystrophy, Facioscapulohumeral - immunology; Muscular Dystrophy, Facioscapulohumeral - metabolism; Myoblasts - cytology; Myoblasts - metabolism; Oligonucleotide Array Sequence Analysis; Primates; Real-Time Polymerase Chain Reaction; Retroelements - genetics; Retrotransposons; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Stem cells; Transcription factors; Transfection
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2011.11.013

Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. [Display omitted] ► DUX4 binds a double homeodomain motif in MaLR retrotransposons and nonrepetitive DNA ► DUX4 activates germline genes, retrotransposons, and immune mediators ► DUX4 target genes are expressed in FSHD skeletal muscle ► DUX4 targets are candidate biomarkers for FSHD and suggest disease mechanisms