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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739093/ https://www.ncbi.nlm.nih.gov/pubmed/31535023 http://dx.doi.org/10.1126/sciadv.aaw7781 |
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author | 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 |
author_facet | 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 |
author_sort | Bosnakovski, Darko |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6739093 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-67390932019-09-18 A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death 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 Sci Adv Research Articles 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. American Association for the Advancement of Science 2019-09-11 /pmc/articles/PMC6739093/ /pubmed/31535023 http://dx.doi.org/10.1126/sciadv.aaw7781 Text en Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles 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 A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death |
title | A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death |
title_full | A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death |
title_fullStr | A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death |
title_full_unstemmed | A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death |
title_short | A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death |
title_sort | novel p300 inhibitor reverses dux4-mediated global histone h3 hyperacetylation, target gene expression, and cell death |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739093/ https://www.ncbi.nlm.nih.gov/pubmed/31535023 http://dx.doi.org/10.1126/sciadv.aaw7781 |
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