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

Abstract

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.

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

“…This gene encodes a double homeobox protein ectopically overexpressed in bursts in patients' myotubes that might activate a number of target genes and induce toxicity (Geng et al 2012) and apoptosis (Bosnakovski et al 2008;Block et al 2013). …”

DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

“…Identification of DUX proteins in germline cells (Geng et al, 2012) suggests a role during development, but little is known of endogenous DUX4 function. Two important DUX4 isoforms are derived from the D4Z4 ORF -DUX4-fl (full-length) that is expressed in germline and stem cells, and the alternatively spliced DUX4-s (short) isoform expressed in some somatic cells at low levels .…”

“…The N-terminus contains two homeodomains with similarity to those of PAX3 and PAX7 (Bosnakovski et al, 2008b), and the C-terminus is a transcriptional activator (Kawamura-Saito et al, 2006). FSHD muscle biopsies and DUX4-expressing myoblast cultures indicate perturbation of Wnt-β-catenin signalling, MYOD regulation, oxidative stress and innate immune response (Banerji et al, 2015a;Block et al, 2013;Bosnakovski et al, 2008a;Celegato et al, 2006;Fitzsimons, 2011;Geng et al, 2012;Winokur et al, 2003b). Transcriptome analysis of endogenous DUX4-expressing cells reveals that DUX4 disrupts pathways involved in RNA metabolism, cell signalling, polarity and migration (Rickard et al, 2015), and nonsense-mediated decay (Feng et al, 2015).…”

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

“…7 Its expression in skeletal muscle activates genes involved in germ line and early stem cell development, as well as specific classes of repeat elements, and overexpression of DUX4 in somatic cells causes cell death. [10][11][12] To cause FSHD, D4Z4 chromatin relaxation must occur on a specific genetic background of chromosome 4 (most often 4A161) that facilitates the production of stable DUX4 mRNA due to the presence of a polymorphic DUX4 polyadenylation signal distal to the D4Z4 repeat array. 8,13 D4Z4 chromatin relaxation on non-permissive chromosomes lacking a DUX4 polyadenylation signal do not cause FSHD in the absence of detectable levels of DUX4 mRNA.…”