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Sci Adv. 2019 Sep 11;5(9):eaaw7781. doi: 10.1126/sciadv.aaw7781. eCollection 2019 Sep.

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

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Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Faculty of Medical Sciences, University Goce Delcev-Štip, Štip 2000, Republic of North Macedonia.
Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, MN 55455, USA.
Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55455, USA.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.


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.

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