Common fragile sites are characterized by histone hypoacetylation
Identifieur interne : 000638 ( Istex/Checkpoint ); précédent : 000637; suivant : 000639Common fragile sites are characterized by histone hypoacetylation
Auteurs : Yanwen Jiang ; Isabelle Lucas ; David J. Young ; Elizabeth M. Davis ; Theodore Karrison [États-Unis] ; Joshua S. Rest [États-Unis] ; Michelle M. Le Beau [États-Unis]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2009.
Abstract
Common fragile sites (CFSs) represent large, highly unstable regions of the human genome. CFS sequences are sensitive to perturbation of replication; however, the molecular basis for the instability at CFSs is poorly understood. We hypothesized that a unique epigenetic pattern may underlie the unusual sensitivity of CFSs to replication interference. To examine this hypothesis, we analyzed chromatin modification patterns within the six human CFSs with the highest levels of breakage, and their surrounding non-fragile regions (NCFSs). Chromatin at most of the CFSs analyzed has significantly less histone acetylation than that of their surrounding NCFSs. Trichostatin A and/or 5-azadeoxycytidine treatment reduced chromosome breakage at CFSs. Furthermore, chromatin at the most commonly expressed CFS, the FRA3B, is more resistant to micrococcal nuclease than that of the flanking non-fragile sequences. These results demonstrate that histone hypoacetylation is a characteristic epigenetic pattern of CFSs, and chromatin within CFSs might be relatively more compact than that of the NCFSs, indicating a role for chromatin conformation in genomic instability at CFSs. Moreover, lack of histone acetylation at CFSs may contribute to the defective response to replication stress characteristic of CFSs, leading to the genetic instability characteristic of this regions.
Url:
DOI: 10.1093/hmg/ddp410
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Rest</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794</wicri:regionArea><wicri:noRegion>NY 11794</wicri:noRegion></affiliation></author><author><name sortKey="Le Beau, Michelle M" sort="Le Beau, Michelle M" uniqKey="Le Beau M" first="Michelle M." last="Le Beau">Michelle M. Le Beau</name><affiliation></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country><wicri:regionArea>To whom correspondence should be addressed. 5841 S. Maryland Ave., MC 2115, Chicago, IL 60637</wicri:regionArea><wicri:noRegion>IL 60637</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published">2009</date><date type="e-published">2009</date><biblScope unit="vol">18</biblScope><biblScope unit="issue">23</biblScope><biblScope unit="page" from="4501">4501</biblScope><biblScope unit="page" to="4512">4512</biblScope></imprint><idno type="ISSN">0964-6906</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Common fragile sites (CFSs) represent large, highly unstable regions of the human genome. CFS sequences are sensitive to perturbation of replication; however, the molecular basis for the instability at CFSs is poorly understood. We hypothesized that a unique epigenetic pattern may underlie the unusual sensitivity of CFSs to replication interference. To examine this hypothesis, we analyzed chromatin modification patterns within the six human CFSs with the highest levels of breakage, and their surrounding non-fragile regions (NCFSs). Chromatin at most of the CFSs analyzed has significantly less histone acetylation than that of their surrounding NCFSs. Trichostatin A and/or 5-azadeoxycytidine treatment reduced chromosome breakage at CFSs. Furthermore, chromatin at the most commonly expressed CFS, the FRA3B, is more resistant to micrococcal nuclease than that of the flanking non-fragile sequences. These results demonstrate that histone hypoacetylation is a characteristic epigenetic pattern of CFSs, and chromatin within CFSs might be relatively more compact than that of the NCFSs, indicating a role for chromatin conformation in genomic instability at CFSs. Moreover, lack of histone acetylation at CFSs may contribute to the defective response to replication stress characteristic of CFSs, leading to the genetic instability characteristic of this regions.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Illinois</li></region><settlement><li>Chicago</li></settlement><orgName><li>Université de Chicago</li></orgName></list><tree><noCountry><name sortKey="Davis, Elizabeth M" sort="Davis, Elizabeth M" uniqKey="Davis E" first="Elizabeth M." last="Davis">Elizabeth M. Davis</name><name sortKey="Jiang, Yanwen" sort="Jiang, Yanwen" uniqKey="Jiang Y" first="Yanwen" last="Jiang">Yanwen Jiang</name><name sortKey="Lucas, Isabelle" sort="Lucas, Isabelle" uniqKey="Lucas I" first="Isabelle" last="Lucas">Isabelle Lucas</name><name sortKey="Young, David J" sort="Young, David J" uniqKey="Young D" first="David J." last="Young">David J. Young</name></noCountry><country name="États-Unis"><region name="Illinois"><name sortKey="Karrison, Theodore" sort="Karrison, Theodore" uniqKey="Karrison T" first="Theodore" last="Karrison">Theodore Karrison</name></region><name sortKey="Le Beau, Michelle M" sort="Le Beau, Michelle M" uniqKey="Le Beau M" first="Michelle M." last="Le Beau">Michelle M. Le Beau</name><name sortKey="Le Beau, Michelle M" sort="Le Beau, Michelle M" uniqKey="Le Beau M" first="Michelle M." last="Le Beau">Michelle M. Le Beau</name><name sortKey="Rest, Joshua S" sort="Rest, Joshua S" uniqKey="Rest J" first="Joshua S." last="Rest">Joshua S. 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