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

被引：343

作者：

Geng, Linda N. ^{[1
]}

Yao, Zizhen ^{[2
]}

Snider, Lauren ^{[1
]}

Fong, Abraham P. ^{[1
]}

Cech, Jennifer N. ^{[1
]}

Young, Janet M. ^{[1
]}

van der Maarel, Silvere M. ^{[3
]}

Ruzzo, Walter L. ^{[4
,5
]}

Gentleman, Robert C. ^{[6
]}

Tawil, Rabi ^{[7
]}

Tapscott, Stephen J. ^{[1
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA

[2] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA

[3] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZA Leiden, Netherlands

[4] Univ Washington, Dept Comp Sci & Engn, Seattle, WA 98105 USA

[5] Univ Washington, Dept Genome Sci, Seattle, WA 98105 USA

[6] Genentech Inc, Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[7] Univ Rochester, Dept Neurol, Rochester, NY 14627 USA

来源：

DEVELOPMENTAL CELL | 2012年 / 22卷 / 01期

关键词：

BETA-DEFENSIN; 3; MUSCULAR-DYSTROPHY; ANTIMICROBIAL PEPTIDES; HUMAN BETA-DEFENSIN-3; HOMEOBOX GENES; CANDIDATE GENE; MUSCLE; EXPRESSION; FSHD; FAMILY;

D O I：

10.1016/j.devcel.2011.11.013

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：38 / 51

页数：14

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