Proposed scheme for FSHD pathogenesis in myoblasts. This cartoon shows some of the main regulatory changes at the myoblast stage that may be determining the FSHD-specific gene expression profile in myoblasts and myotubes. DUX4-fl RNA is found at extremely low levels in FSHD and control myoblasts and myotubes but not in the corresponding control cells. The double-headed arrows indicate that these regulatory changes can reinforce each other. TF, transcription factors. RNAi, RNA interference; *, the activation of DUX4-fl expression in FSHD at the satellite cell stage is proposed to occur at or before activation of FSHD satellite cells and is not yet tested.