The DUX4 model of FSHD.

<p>(A) A model of the human system, which represents a summary of published work relevant to understanding FRG1 and DUX4 in relation to FSHD supplied to aid the reader with context, showing the FSHD-associated human chromosome 4q35 D4Z4 macrosatellite in healthy (upper) and FSHD (lower) subjects. In healthy subjects, the D4Z4 array consists of between 11 and ~120 D4Z4 repeat units (RU) and is epigenetically repressed (black lollipops). FRG1 is ubiquitously expressed, but there is no (or very little) polyadenylated DUX4-fl mRNA expression. In FSHD1 subjects, the D4Z4 array consists of between 1 and 10 D4Z4 RU, is epigenetically derepressed (yellow lollipops), and a significantly higher fraction of cells than in healthy subjects express polyadenlylated DUX4-fl mRNA. The DUX4-FL protein, a transcription factor that regulates many genes, can bind to an enhancer located in intron 2 of <i>FRG1</i>, and expression levels of FRG1 are moderately increased in these DUX4-FL expressing cells [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150938#pone.0150938.ref034" target="_blank">34</a>]. (B) The polyadenylated DUX4-fl mRNA is derived from the distal repeat of the D4Z4 array. There are two potential translation start sites for DUX4-fl, termed MKG and MAL. Transgenic <i>Drosophila UAS-DUX4-fl</i><sup><i>MKG</i></sup> and <i>UAS-DUX4-fl</i><sup><i>MAL</i></sup> contain the coding sequence, codon optimized for <i>Drosophila</i>, from the indicated start codon through the stop codon (red *) in exon 1. Please see the following reviews for relevant references relating to FSHD depicted in this figure [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150938#pone.0150938.ref017" target="_blank">17</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150938#pone.0150938.ref021" target="_blank">21</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150938#pone.0150938.ref024" target="_blank">24</a>].</p>