A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death
Autor: | Ce Yuan, Ajit Jadhav, Darko Bosnakovski, Michael A. Walters, Erik A. Toso, Elizabeth T. Ener, Sithara T. Sunny, Meiricris T. Silva, Michael Kyba, Ziyou Cui |
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Rok vydání: | 2019 |
Předmět: |
Mice
Transgenic Diseases and Disorders Histones Myoblasts 03 medical and health sciences Histone H3 Mice 0302 clinical medicine DUX4 medicine Facioscapulohumeral muscular dystrophy Animals Humans EP300 Histone H3 acetylation Muscle Skeletal Transcription factor Cells Cultured Research Articles 030304 developmental biology Histone Acetyltransferases Homeodomain Proteins 0303 health sciences Multidisciplinary Cell Death Chemistry SciAdv r-articles Acetylation Human Genetics medicine.disease Muscular Dystrophy Facioscapulohumeral 3. Good health Cell biology Disease Models Animal Gene Expression Regulation Maternal to zygotic transition Female E1A-Associated p300 Protein Protein Processing Post-Translational 030217 neurology & neurosurgery Research Article |
Zdroj: | Science Advances |
ISSN: | 2375-2548 |
Popis: | DUX4 drives global histone H3 hyperacetylation; and a new P300 inhibitor, iP300w, blocks DUX4-mediated transcription and toxicity. 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. |
Databáze: | OpenAIRE |
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