Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense mutations suppress gene silencing associated with position effect variegation

For many years it has been noted that there is a correlation between acetylation of histones and an increase in transcriptional activity. One prediction, based on this correlation, is that hypomorphic or null mutations in histone deacetylase genes should lead to increased levels of histone acetylati...

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Bibliographic Details
Published in:Genetics (Austin) 2000-02, Vol.154 (2), p.657-668
Main Authors: Mottus, R, Sobel, R.E, Grigliatti, T.A
Format: Article
Language:English
Subjects:
Alleles
Amino Acid Sequence
amino acid sequences
amino acid substitutions
Animals
Blotting, Northern
color
compound eyes
Deoxyribonucleic acid
DNA
Drosophila melanogaster
Drosophila melanogaster - enzymology
esterases
Female
gene expression
Gene Silencing
genes
genetic regulation
Genetics
HDAC1 gene
histone deacetylase
Histone Deacetylases - genetics
histones
Humans
lethal genes
Male
messenger RNA
Molecular Sequence Data
Mutation
Mutation, Missense
phenotype
position effect
Sequence Homology, Amino Acid
transcriptional silencing
variegation
viability
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Summary:For many years it has been noted that there is a correlation between acetylation of histones and an increase in transcriptional activity. One prediction, based on this correlation, is that hypomorphic or null mutations in histone deacetylase genes should lead to increased levels of histone acetylation and result in increased levels of transcription. It was therefore surprising when it was reported, in both yeast and fruit flies, that mutations that reduced or eliminated a histone deacetylase resulted in transcriptional silencing of genes subject to telomeric and heterochromatic position effect variegation (PEV). Here we report the first mutational analysis of a histone deacetylase in a multicellular eukaryote by examining six new mutations in HDAC1 of Drosophila melanogaster. We observed a suite of phenotypes accompanying the mutations consistent with the notion that HDAC1 acts as a global transcriptional regulator. However, in contrast to recent findings, here we report that specific missense mutations in the structural gene of HDAC1 suppress the silencing of genes subject to PEV. We propose that the missense mutations reported here are acting as antimorphic mutations that "poison" the deacetylase complex and propose a model that accounts for the various phenotypes associated with lesions in the deacetylase locus.
ISSN:0016-6731
1943-2631
1943-2631
DOI:10.1093/genetics/154.2.657