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

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 cytotoxicit...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2019-09, Vol.5 (9), p.eaaw7781-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: Article
Language:English
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aaw7781