title: Common fragile sites are characterized by histone hypoacetylation.
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.
authors.affiliation: Committee on Cancer Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lucas
authors.forename: David J
authors.initials: DJ
authors.lastname: Young
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davis
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Rest
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
mesh_terms: D000107:Acetylation; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D043283:Chromosome Fragile Sites; D044127:Epigenesis, Genetic; D005260:Female; D015894:Genome, Human; D042822:Genomic Instability; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans
chemical_list: D002843:Chromatin; D006657:Histones