Histone deacetylase complexes promote trinucleotide repeat expansions.

Expansions of DNA trinucleotide repeats cause at least 17 inherited neurodegenerative diseases, such as Huntington's disease. Expansions can occur at frequencies approaching 100% in affected families and in transgenic mice, suggesting that specific cellular proteins actively promote (favor) exp...

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Autores principales:	Kim Debacker, Aisling Frizzell, Olive Gleeson, Lucy Kirkham-McCarthy, Tony Mertz, Robert S Lahue
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b927da874127465b9d9a9362fd86d0c4
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spelling	oai:doaj.org-article:b927da874127465b9d9a9362fd86d0c42021-11-18T05:36:46ZHistone deacetylase complexes promote trinucleotide repeat expansions.1544-91731545-788510.1371/journal.pbio.1001257https://doaj.org/article/b927da874127465b9d9a9362fd86d0c42012-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22363205/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Expansions of DNA trinucleotide repeats cause at least 17 inherited neurodegenerative diseases, such as Huntington's disease. Expansions can occur at frequencies approaching 100% in affected families and in transgenic mice, suggesting that specific cellular proteins actively promote (favor) expansions. The inference is that expansions arise due to the presence of these promoting proteins, not their absence, and that interfering with these proteins can suppress expansions. The goal of this study was to identify novel factors that promote expansions. We discovered that specific histone deacetylase complexes (HDACs) promote CTG•CAG repeat expansions in budding yeast and human cells. Mutation or inhibition of yeast Rpd3L or Hda1 suppressed up to 90% of expansions. In cultured human astrocytes, expansions were suppressed by 75% upon inhibition or knockdown of HDAC3, whereas siRNA against the histone acetyltransferases CBP/p300 stimulated expansions. Genetic and molecular analysis both indicated that HDACs act at a distance from the triplet repeat to promote expansions. Expansion assays with nuclease mutants indicated that Sae2 is one of the relevant factors regulated by Rpd3L and Hda1. The causal relationship between HDACs and expansions indicates that HDACs can promote mutagenesis at some DNA sequences. This relationship further implies that HDAC3 inhibitors being tested for relief of expansion-associated gene silencing may also suppress somatic expansions that contribute to disease progression.Kim DebackerAisling FrizzellOlive GleesonLucy Kirkham-McCarthyTony MertzRobert S LahuePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 10, Iss 2, p e1001257 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Kim Debacker Aisling Frizzell Olive Gleeson Lucy Kirkham-McCarthy Tony Mertz Robert S Lahue Histone deacetylase complexes promote trinucleotide repeat expansions.
description	Expansions of DNA trinucleotide repeats cause at least 17 inherited neurodegenerative diseases, such as Huntington's disease. Expansions can occur at frequencies approaching 100% in affected families and in transgenic mice, suggesting that specific cellular proteins actively promote (favor) expansions. The inference is that expansions arise due to the presence of these promoting proteins, not their absence, and that interfering with these proteins can suppress expansions. The goal of this study was to identify novel factors that promote expansions. We discovered that specific histone deacetylase complexes (HDACs) promote CTG•CAG repeat expansions in budding yeast and human cells. Mutation or inhibition of yeast Rpd3L or Hda1 suppressed up to 90% of expansions. In cultured human astrocytes, expansions were suppressed by 75% upon inhibition or knockdown of HDAC3, whereas siRNA against the histone acetyltransferases CBP/p300 stimulated expansions. Genetic and molecular analysis both indicated that HDACs act at a distance from the triplet repeat to promote expansions. Expansion assays with nuclease mutants indicated that Sae2 is one of the relevant factors regulated by Rpd3L and Hda1. The causal relationship between HDACs and expansions indicates that HDACs can promote mutagenesis at some DNA sequences. This relationship further implies that HDAC3 inhibitors being tested for relief of expansion-associated gene silencing may also suppress somatic expansions that contribute to disease progression.
format	article
author	Kim Debacker Aisling Frizzell Olive Gleeson Lucy Kirkham-McCarthy Tony Mertz Robert S Lahue
author_facet	Kim Debacker Aisling Frizzell Olive Gleeson Lucy Kirkham-McCarthy Tony Mertz Robert S Lahue
author_sort	Kim Debacker
title	Histone deacetylase complexes promote trinucleotide repeat expansions.
title_short	Histone deacetylase complexes promote trinucleotide repeat expansions.
title_full	Histone deacetylase complexes promote trinucleotide repeat expansions.
title_fullStr	Histone deacetylase complexes promote trinucleotide repeat expansions.
title_full_unstemmed	Histone deacetylase complexes promote trinucleotide repeat expansions.
title_sort	histone deacetylase complexes promote trinucleotide repeat expansions.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/b927da874127465b9d9a9362fd86d0c4
work_keys_str_mv	AT kimdebacker histonedeacetylasecomplexespromotetrinucleotiderepeatexpansions AT aislingfrizzell histonedeacetylasecomplexespromotetrinucleotiderepeatexpansions AT olivegleeson histonedeacetylasecomplexespromotetrinucleotiderepeatexpansions AT lucykirkhammccarthy histonedeacetylasecomplexespromotetrinucleotiderepeatexpansions AT tonymertz histonedeacetylasecomplexespromotetrinucleotiderepeatexpansions AT robertslahue histonedeacetylasecomplexespromotetrinucleotiderepeatexpansions
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Histone deacetylase complexes promote trinucleotide repeat expansions.

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