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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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Autores principales: 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.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2573955/
https://www.ncbi.nlm.nih.gov/pubmed/19008940
http://dx.doi.org/10.1371/journal.pgen.1000257
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author 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.
author_facet 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.
author_sort Libby, Randell T.
collection PubMed
description 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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spelling pubmed-25739552008-11-14 CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination 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. PLoS Genet Research Article 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. Public Library of Science 2008-11-14 /pmc/articles/PMC2573955/ /pubmed/19008940 http://dx.doi.org/10.1371/journal.pgen.1000257 Text en Libby et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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.
CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination
title CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination
title_full CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination
title_fullStr CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination
title_full_unstemmed CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination
title_short CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination
title_sort ctcf cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2573955/
https://www.ncbi.nlm.nih.gov/pubmed/19008940
http://dx.doi.org/10.1371/journal.pgen.1000257
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