title: CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination.
abstract: At least 25 inherited disorders in humans result from microsatellite repeat expansion. Dramatic variation in repeat instability occurs at different disease loci and between different tissues; however, cis-elements and trans-factors regulating the instability process remain undefined. Genomic fragments from the human spinocerebellar ataxia type 7 (SCA7) locus, containing a highly unstable CAG tract, were previously introduced into mice to localize cis-acting "instability elements," and revealed that genomic context is required for repeat instability. The critical instability-inducing region contained binding sites for CTCF -- a regulatory factor implicated in genomic imprinting, chromatin remodeling, and DNA conformation change. To evaluate the role of CTCF in repeat instability, we derived transgenic mice carrying SCA7 genomic fragments with CTCF binding-site mutations. We found that CTCF binding-site mutation promotes triplet repeat instability both in the germ line and in somatic tissues, and that CpG methylation of CTCF binding sites can further destabilize triplet repeat expansions. As CTCF binding sites are associated with a number of highly unstable repeat loci, our findings suggest a novel basis for demarcation and regulation of mutational hot spots and implicate CTCF in the modulation of genetic repeat instability.
authors.affiliation: Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA, USA.
authors.forename: Randell T
authors.initials: RT
authors.lastname: Libby
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Hagerman
authors.forename: Victor V
authors.initials: VV
authors.lastname: Pineda
authors.forename: Rachel
authors.initials: R
authors.lastname: Lau
authors.forename: Diane H
authors.initials: DH
authors.lastname: Cho
authors.forename: Sandy L
authors.initials: SL
authors.lastname: Baccam
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Axford
authors.forename: John D
authors.initials: JD
authors.lastname: Cleary
authors.forename: James M
authors.initials: JM
authors.lastname: Moore
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: Galina N
authors.initials: GN
authors.lastname: Filippova
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pearson
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins