Figure 4. DUX4 and NMD form a feedback loop.
(A) Schematic of potential double-negative feedback loop between DUX4 and NMD, in which DUX4 inhibits NMD and NMD degrades DUX4 mRNA. (B) Levels of endogenously transcribed DUX4 mRNA following control treatment or ectopic DUX4 expression, measured 2 days after the initiation of myogenesis in FSHD1 (54-2) and FSHD2 (MB200) cells. (C) Relative levels of transcripts from the Gl-DUX4-Intron2(+) and Gl-DUX4-Intron2(−) constructs following control treatment or ectopic DUX4 expression in normal myoblasts (54-1 cells). For each construct, data are normalized such that the siControl treatment is 1. Error bars, standard deviation. (D) Schematic of potential model of interactions between DUX4 and NMD in healthy (top) and FSHD (bottom) muscle cells. In healthy cells, DUX4 mRNA is efficiently degraded by NMD; in FSHD cells, DUX4 triggers proteolytic degradation of UPF1 and inhibits NMD, resulting in the accumulation of DUX4 mRNA and protein.