CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination

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 fragmen...

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Bibliographic Details
Published in:PLoS genetics 2008-11, Vol.4 (11), p.e1000257-e1000257
Main Authors: Libby, Randell T, Hagerman, Katharine A, Pineda, Victor V, Lau, Rachel, Cho, Diane H, Baccam, Sandy L, Axford, Michelle M, Cleary, John D, Moore, James M, Sopher, Bryce L, Tapscott, Stephen J, Filippova, Galina N, Pearson, Christopher E, La Spada, Albert R
Format: Article
Language:English
Subjects:
Animals
Ataxin-7
Binding Sites
Binding sites (Biochemistry)
Causes of
CCCTC-Binding Factor
Chromosome abnormalities
Complications and side effects
DNA Methylation
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
DNA-ligand interactions
Epigenesis, Genetic
Female
Genetic regulation
Genetics
Genetics and Genomics/Disease Models
Genetics and Genomics/Epigenetics
Genetics and Genomics/Medical Genetics
Genomic Instability
Humans
Male
Medical research
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurological Disorders/Neurogenetics
Physiological aspects
Proteins
Regulatory Sequences, Nucleic Acid
Repressor Proteins - genetics
Repressor Proteins - metabolism
Rodents
Spinocerebellar Ataxias - genetics
Trinucleotide Repeat Expansion
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1000257