Figure 6.

Hypothesized intrachromosomal communication by chromatin looping. (A) A disease-associated long-distance loop is hypothesized to form when the D4Z4 repeat array is contracted to less than 11 repeat units, leading to inappropriate expression in cis of an unelucidated 4q35 FSHD master gene (thick brown line). These abnormal looping interactions might upregulate transcription of the FSHD master gene in cis by direct chromatin-to-chromatin contact and/or alteration of the chromatin protein composition of the promoter of the FSHD master gene. The hypothesized long-distance looping may include interactions with the sequences distal to D4Z4, which are shown as a thick light blue line, ∼15–25 kb ending at the telomeric TTAGGG repeats (5,52). (B) Intra-array looping for arrays with more than 10 repeat units would sequester the proximal end of D4Z4 so that it would not be available for pathogenic long-distance looping. Size-dependent, topological constraints on intra-array looping could explain why the disease severity is often lower when the 4q35 array is in the 8–10 unit range relative to the 1–4 unit range. Looping interactions of D4Z4 sequences might involve G-quadruplexes.