In this study, we showed that expression of MBD3L2 was sufficient to amplify DUX4 expression in FSHD cells and knockdown using an shRNA that targets the entire family showed that expression of the MBD3L family was necessary for the full induction of DUX4 expression in FSHD myotubes. Here, MBD3L2 is linked to facioscapulohumeral muscular dystrophy.