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The DUX4 model of FSHD.

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posted on 2016-03-04, 07:29 authored by Takako I. Jones, Megan Parilla, Peter L. Jones

(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 FRG1, and expression levels of FRG1 are moderately increased in these DUX4-FL expressing cells [34]. (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 Drosophila UAS-DUX4-flMKG and UAS-DUX4-flMAL contain the coding sequence, codon optimized for Drosophila, 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 [17, 21, 24].

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