CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination
Open accessAbstract
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.
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Disruption of a CTCF binding site at the Atxn7 locus leads to increased somatic and germline repeat instability in a transgenic mouse model of spinocerebellar ataxia 7.
“Disruption of a CTCF binding site at the Atxn7 locus leads to increased somatic and germline repeat instability in a transgenic mouse model of spinocerebellar ataxia 7 (Libby et al., 2008).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Libby et al., 2008
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“Our observations add a 3D component to the locus-specific evidence that STR instability is linked to alterations of CTCF occupancy (Brock et al., 1999; Cleary et al., 2010; Filippova et al., 2001; Libby et al., 2008; Sopher et al., 2011).”
BackgroundCleary, J. D., Tomé, S., López Castel, A., Panigrahi, G. B., Foiry, L., Hagerman, K. A., Sroka, H., Chitayat, D., Gourdon, G., & Pearson, C. E. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1876 · Cited by 69 · see citing works
Self-citation
- Authors
- Libby, R. T., Hagerman, K. A., Pineda, V. V., Lau, R., Cho, D. H., Baccam, S. L., Axford, M. M., Cleary, J. D., Moore, J. M., Sopher, B. L., Tapscott, S. J., Filippova, G. N., Pearson, C. E., & La Spada, A. R.
- Affiliations
- University of Washington Medical Center (US)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Fred Hutch Cancer Center (US)
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-11-14
- Volume
- 4
- Issue
- 11
- Pages
- e1000257
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC2573955
- OpenAlex
- W2053187937
- Cited by
- 138
- References
- 48
- Citations by year
- 2025: 3 · 2024: 13 · 2022: 3 · 2021: 3 · 2020: 7 · 2019: 9 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 9 · 2014: 10 · 2013: 13 · 2012: 12
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Muscular Dystrophy Association
- University of Toronto
- Hospital for Sick Children
- National Institutes of Health (AG-00057)
- Canadian Institutes of Health Research
- National Institute on Aging (AG 00057, T32AG000057)
- National Eye Institute (EY14061, R01EY014061)
- National Cancer Institute (R01CA068360, CA68360)
- National Institute of General Medical Sciences (GM59356, R01GM059356)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR050741, AR4203)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- CTCF, trinucleotide repeat instability, spinocerebellar ataxia type 7, CAG repeat, cis-regulation, CpG methylation, mutational hotspots, transgenic mice, epigenetic regulation, somatic instability
- MeSH terms
- Ataxin-7, CCCTC-Binding Factor, Animals, Binding Sites, DNA-Binding Proteins, Female, Humans, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Regulatory Sequences, Nucleic Acid, Repressor Proteins, DNA Methylation, Trinucleotide Repeat Expansion, Spinocerebellar Ataxias, Genomic Instability, Epigenesis, Genetic, Mice
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