histone deacetylase complexes promote trinucleotide repeat expansions组蛋白脱乙酰酶复合物促进三核苷酸重复扩张.pdfVIP
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histone deacetylase complexes promote trinucleotide repeat expansions组蛋白脱乙酰酶复合物促进三核苷酸重复扩张
Histone Deacetylase Complexes Promote Trinucleotide
Repeat Expansions
. .
Kim Debacker , Aisling Frizzell , Olive Gleeson, Lucy Kirkham-McCarthy, Tony Mertz, Robert S. Lahue*
Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
Abstract
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 CTGNCAG 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 contr
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