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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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Published in: | Genetics (Austin) 2000-02, Vol.154 (2), p.657-668 |
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description | 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. |
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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.</description><identifier>ISSN: 0016-6731</identifier><identifier>ISSN: 1943-2631</identifier><identifier>EISSN: 1943-2631</identifier><identifier>DOI: 10.1093/genetics/154.2.657</identifier><identifier>PMID: 10655219</identifier><identifier>CODEN: GENTAE</identifier><language>eng</language><publisher>United States: Genetics Soc America</publisher><subject>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</subject><ispartof>Genetics (Austin), 2000-02, Vol.154 (2), p.657-668</ispartof><rights>Copyright Genetics Society of America Feb 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-ecbce88cdfd254049751066acb0b3bfdd6b0421de5ffc2275341c1c886da08d73</citedby><cites>FETCH-LOGICAL-c511t-ecbce88cdfd254049751066acb0b3bfdd6b0421de5ffc2275341c1c886da08d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10655219$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mottus, R</creatorcontrib><creatorcontrib>Sobel, R.E</creatorcontrib><creatorcontrib>Grigliatti, T.A</creatorcontrib><title>Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense mutations suppress gene silencing associated with position effect variegation</title><title>Genetics (Austin)</title><addtitle>Genetics</addtitle><description>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.</description><subject>Alleles</subject><subject>Amino Acid Sequence</subject><subject>amino acid sequences</subject><subject>amino acid substitutions</subject><subject>Animals</subject><subject>Blotting, Northern</subject><subject>color</subject><subject>compound eyes</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drosophila melanogaster</subject><subject>Drosophila melanogaster - enzymology</subject><subject>esterases</subject><subject>Female</subject><subject>gene expression</subject><subject>Gene Silencing</subject><subject>genes</subject><subject>genetic regulation</subject><subject>Genetics</subject><subject>HDAC1 gene</subject><subject>histone deacetylase</subject><subject>Histone Deacetylases - genetics</subject><subject>histones</subject><subject>Humans</subject><subject>lethal genes</subject><subject>Male</subject><subject>messenger RNA</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>phenotype</subject><subject>position effect</subject><subject>Sequence Homology, Amino Acid</subject><subject>transcriptional silencing</subject><subject>variegation</subject><subject>viability</subject><issn>0016-6731</issn><issn>1943-2631</issn><issn>1943-2631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><recordid>eNpdkc2O1DAQhCMEYoeFF-AAFgduM-t24vxwQELL8iMt4gB7thynk3iVxMHt7GiehlddDzPAwMV98Fel7qokeQ58A7xKLzqcMFhDFyCzjdjksniQrKDK0rXIU3iYrDiHfJ0XKZwlT4huOed5JcvHyRnwXEoB1Sr5-WUJOlg36YHp-OzIEnMt06y3FNyErEFtMOwGTcjsxN57R27u7aDZiIOeXKcpoH_DRkuEU4TGoyMxWubZIxHbb8rIDjgZO3VMEzljdcCGbW3o2ezI7hUM2xZNYHfaW-x-mTxNHrV6IHx2nOfJzYer75ef1tdfP36-fHe9NhIgrNHUBsvSNG0jZMazqpDxxlybmtdp3TZNXvNMQIOybY0QhUwzMGDKMm80L5siPU_eHnznpR6xMTgFrwc1eztqv1NOW_Xvz2R71bk7BVnOY-TR4PXRwLsfC1JQMRCDQ4wI3UIKiqwQAsoIvvoPvHWLj9GTEpCBEDLfQ-IAmRg3eWz_bAJc7ctXv8tXsXwlVCw_il6c3nAiObT9d8fedv3WelQ06mGIOKjtdnvq9PIAttop3XlL6uab4JByUWWylGV6D2Ehylg</recordid><startdate>20000201</startdate><enddate>20000201</enddate><creator>Mottus, R</creator><creator>Sobel, R.E</creator><creator>Grigliatti, T.A</creator><general>Genetics Soc America</general><general>Genetics Society of America</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>4T-</scope><scope>4U-</scope><scope>7QP</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20000201</creationdate><title>Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense mutations suppress gene silencing associated with position effect variegation</title><author>Mottus, R ; Sobel, R.E ; Grigliatti, T.A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-ecbce88cdfd254049751066acb0b3bfdd6b0421de5ffc2275341c1c886da08d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Alleles</topic><topic>Amino Acid Sequence</topic><topic>amino acid sequences</topic><topic>amino acid substitutions</topic><topic>Animals</topic><topic>Blotting, Northern</topic><topic>color</topic><topic>compound eyes</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Drosophila melanogaster</topic><topic>Drosophila melanogaster - enzymology</topic><topic>esterases</topic><topic>Female</topic><topic>gene expression</topic><topic>Gene Silencing</topic><topic>genes</topic><topic>genetic regulation</topic><topic>Genetics</topic><topic>HDAC1 gene</topic><topic>histone deacetylase</topic><topic>Histone Deacetylases - genetics</topic><topic>histones</topic><topic>Humans</topic><topic>lethal genes</topic><topic>Male</topic><topic>messenger RNA</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>phenotype</topic><topic>position effect</topic><topic>Sequence Homology, Amino Acid</topic><topic>transcriptional silencing</topic><topic>variegation</topic><topic>viability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mottus, R</creatorcontrib><creatorcontrib>Sobel, R.E</creatorcontrib><creatorcontrib>Grigliatti, T.A</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Docstoc</collection><collection>University Readers</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genetics (Austin)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mottus, R</au><au>Sobel, R.E</au><au>Grigliatti, T.A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense mutations suppress gene silencing associated with position effect variegation</atitle><jtitle>Genetics (Austin)</jtitle><addtitle>Genetics</addtitle><date>2000-02-01</date><risdate>2000</risdate><volume>154</volume><issue>2</issue><spage>657</spage><epage>668</epage><pages>657-668</pages><issn>0016-6731</issn><issn>1943-2631</issn><eissn>1943-2631</eissn><coden>GENTAE</coden><abstract>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. 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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 |
title | Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense mutations suppress gene silencing associated with position effect variegation |
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