BAZ1A promotes expression of DUX4-fl and its lncRNA activator DBE-T in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic silencing of a D4Z4 macrosatellite array, leading to pathogenic misexpression of DUX4 in skeletal muscle. Therapeutic development of small molecule drugs for FSHD has been hampered by screens that yield key myogenic regulators as candidates and a lack of mechanistic knowledge regarding their effects on DUX4. To uncover more specific targets, we performed a candidate-based screen which identified several epigenetic facilitators of DUX4 expression in primary FSHD myocytes, including the chromatin remodeling factor BAZ1A. Here, we used a compound that we recently identified as a BAZ1A inhibitor and potent DUX4 suppressor to interrogate the role of BAZ1A at the FSHD locus. Our data suggest a model in which BAZ1A binds to D4Z4 in FSHD muscle, changing the chromatin landscape of the array. BAZ1A binding leads to reduced occupancy of the HP1 repressor, increased occupancy of the p300 coactivator, and increased H3K27 acetylation, promoting transcription of both DUX4 and the long non-coding RNA DBE-T from the disease locus. DBE-T, in turn, recruits the histone methyltransferase ASH1L, which establishes H3K36 methylation in cis, further promoting DUX4 transcription. BAZ1A inhibition disrupts this powerful feed-forward loop, supporting the development of more metabolically stable inhibitors. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/732407v1_ufig1.gif" ALT="Figure 1000"> View larger version (28K): org.highwire.dtl.DTLVardef@13bba8dorg.highwire.dtl.DTLVardef@5485c4org.highwire.dtl.DTLVardef@11a2e02org.highwire.dtl.DTLVardef@1c2a6b2_HPS_FORMAT_FIGEXP M_FIG C_FIG