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The H3.3K27M oncohistone antagonizes reprogramming in Drosophila

Development proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In certain cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of pr...

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Autores principales: Ahmad, Kami, Henikoff, Steven
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320987/
https://www.ncbi.nlm.nih.gov/pubmed/34280185
http://dx.doi.org/10.1371/journal.pgen.1009225
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author Ahmad, Kami
Henikoff, Steven
author_facet Ahmad, Kami
Henikoff, Steven
author_sort Ahmad, Kami
collection PubMed
description Development proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In certain cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of previously silenced genes, and such developmental aberrations are thought to underlie a variety of cancers. Here, we express the wing-specific Vestigial master regulator to reprogram the developing eye, and test the role of silencing in reprogramming using an H3.3K27M oncohistone mutation that dominantly inhibits histone H3K27 trimethylation. We find that production of the oncohistone blocks eye-to-wing reprogramming. CUT&Tag chromatin profiling of mutant tissues shows that H3K27me3 of domains is generally reduced upon oncohistone production, suggesting that a previous developmental program must be silenced for effective transformation. Strikingly, Vg and H3.3K27M synergize to stimulate overgrowth of eye tissue, a phenotype that resembles that of mutations in Polycomb silencing components. Transcriptome profiling of elongating RNA Polymerase II implicates the mis-regulation of signaling factors in overgrowth. Our results demonstrate that growth dysregulation can result from the simple combination of crippled silencing and transcription factor mis-expression, an effect that may explain the origins of oncohistone-bearing cancers.
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spelling pubmed-83209872021-07-31 The H3.3K27M oncohistone antagonizes reprogramming in Drosophila Ahmad, Kami Henikoff, Steven PLoS Genet Research Article Development proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In certain cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of previously silenced genes, and such developmental aberrations are thought to underlie a variety of cancers. Here, we express the wing-specific Vestigial master regulator to reprogram the developing eye, and test the role of silencing in reprogramming using an H3.3K27M oncohistone mutation that dominantly inhibits histone H3K27 trimethylation. We find that production of the oncohistone blocks eye-to-wing reprogramming. CUT&Tag chromatin profiling of mutant tissues shows that H3K27me3 of domains is generally reduced upon oncohistone production, suggesting that a previous developmental program must be silenced for effective transformation. Strikingly, Vg and H3.3K27M synergize to stimulate overgrowth of eye tissue, a phenotype that resembles that of mutations in Polycomb silencing components. Transcriptome profiling of elongating RNA Polymerase II implicates the mis-regulation of signaling factors in overgrowth. Our results demonstrate that growth dysregulation can result from the simple combination of crippled silencing and transcription factor mis-expression, an effect that may explain the origins of oncohistone-bearing cancers. Public Library of Science 2021-07-19 /pmc/articles/PMC8320987/ /pubmed/34280185 http://dx.doi.org/10.1371/journal.pgen.1009225 Text en © 2021 Ahmad, Henikoff https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ahmad, Kami
Henikoff, Steven
The H3.3K27M oncohistone antagonizes reprogramming in Drosophila
title The H3.3K27M oncohistone antagonizes reprogramming in Drosophila
title_full The H3.3K27M oncohistone antagonizes reprogramming in Drosophila
title_fullStr The H3.3K27M oncohistone antagonizes reprogramming in Drosophila
title_full_unstemmed The H3.3K27M oncohistone antagonizes reprogramming in Drosophila
title_short The H3.3K27M oncohistone antagonizes reprogramming in Drosophila
title_sort h3.3k27m oncohistone antagonizes reprogramming in drosophila
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320987/
https://www.ncbi.nlm.nih.gov/pubmed/34280185
http://dx.doi.org/10.1371/journal.pgen.1009225
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