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:	Kami Ahmad, Steven Henikoff
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/abfbcd07cee24b55be3bd187a758fcfb
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spelling	oai:doaj.org-article:abfbcd07cee24b55be3bd187a758fcfb2021-12-02T20:02:45ZThe H3.3K27M oncohistone antagonizes reprogramming in Drosophila.1553-73901553-740410.1371/journal.pgen.1009225https://doaj.org/article/abfbcd07cee24b55be3bd187a758fcfb2021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009225https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Development 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.Kami AhmadSteven HenikoffPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009225 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Kami Ahmad Steven Henikoff The H3.3K27M oncohistone antagonizes reprogramming in Drosophila.
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.
format	article
author	Kami Ahmad Steven Henikoff
author_facet	Kami Ahmad Steven Henikoff
author_sort	Kami Ahmad
title	The H3.3K27M oncohistone antagonizes reprogramming in Drosophila.
title_short	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_sort	h3.3k27m oncohistone antagonizes reprogramming in drosophila.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/abfbcd07cee24b55be3bd187a758fcfb
work_keys_str_mv	AT kamiahmad theh33k27moncohistoneantagonizesreprogrammingindrosophila AT stevenhenikoff theh33k27moncohistoneantagonizesreprogrammingindrosophila AT kamiahmad h33k27moncohistoneantagonizesreprogrammingindrosophila AT stevenhenikoff h33k27moncohistoneantagonizesreprogrammingindrosophila
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The H3.3K27M oncohistone antagonizes reprogramming in Drosophila.

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