Figure 2.

D4Z4 regulates local chromatin structure and expression of surrounding genes via long noncoding RNA. Healthy individuals carry between 11 and 150 copies of D4Z4 macrosatellite in the subtelomeric regions of chromosome 4 (4q35). D4Z4 repeats are highly methylated and enriched in H3K9me3. D4Z4 repeats are targets of Polycomb group proteins (PcG), with a resulting repressive chromatin structure and surrounding genes in transcriptionally silent state. In patients with facioscapulohumeral dystrophy 1 (FSHD1) there is a reduction of D4Z4 copy number to between 1 and 10 copies. The contracted allele loses heterochromatin features (DNA methylation, H3K9me3, H3K27me3) and expresses a long noncoding RNA DBE-T, from a promoter distal to the repeat array, that binds and recruits Tritorax group protein Ash1L in cis, resulting in H3 lysine 36 dimethylation and long-range gene up regulation. In addition, transcription within each repeat unit was reported to occur bidirectionally, indicated by red (sense transcription) and blue (antisense transcription) arrows. Sense and antisense transcripts originate from promoters mapped upstream and downstream of DUX4 ORF, respectively, and are transcribed through multiple D4Z4 repeat units. Those transcripts are suggested to give rise to small ncRNAs. Model design based on,ref. 57, 59 and 60.