A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death

• Published in: Science advances Vol. 5; no. 9; p. eaaw7781
• Main Authors: Bosnakovski, Darko, da Silva, Meiricris T, Sunny, Sithara T, Ener, Elizabeth T, Toso, Erik A, Yuan, Ce, Cui, Ziyou, Walters, Michael A, Jadhav, Ajit, Kyba, Michael
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.09.2019
• Subjects: Acetylation; Animals; Cell Death; Cells, Cultured; Disease Models, Animal; Diseases and Disorders; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; Female; Gene Expression Regulation; Histones - genetics; Histones - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Human Genetics; Humans; Mice; Mice, Transgenic; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Dystrophy, Facioscapulohumeral - metabolism; Muscular Dystrophy, Facioscapulohumeral - pathology; Myoblasts - metabolism; Myoblasts - pathology; Protein Processing, Post-Translational; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aaw7781

Facioscapulohumeral muscular dystrophy (FSHD) results from mutations causing overexpression of the transcription factor, DUX4, which interacts with the histone acetyltransferases, EP300 and CBP. We describe the activity of a new spirocyclic EP300/CBP inhibitor, iP300w, which inhibits the cytotoxicity of the DUX4 protein and reverses the overexpression of most DUX4 target genes, in engineered cell lines and FSHD myoblasts, as well as in an FSHD animal model. In evaluating the effect of iP300w on global histone H3 acetylation, we discovered that DUX4 overexpression leads to a dramatic global increase in the total amount of acetylated histone H3. This unexpected effect requires the C-terminus of DUX4, is conserved with mouse Dux, and may facilitate zygotic genome activation. This global increase in histone H3 acetylation is reversed by iP300w, highlighting the central role of EP300 and CBP in the transcriptional mechanism underlying DUX4 cytotoxicity and the translational potential of blocking this interaction.