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PMID: 19008940 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

PLoS genetics ·Vol. 4 ·No. 11 ·2008-11-00 ·Pages e1000257

Libby RT, Hagerman KA, Pineda VV, Lau R, Cho DH, Baccam SL, Axford MM, Cleary JD, Moore JM, Sopher BL, Tapscott SJ, Filippova GN, Pearson CE, La Spada AR

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.

MeSH Terms
Animals Ataxin-7 Binding Sites CCCTC-Binding Factor DNA Methylation DNA-Binding Proteins/genetics,metabolism Epigenesis, Genetic Female Genomic Instability Humans Male Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Transgenic Mutation Nerve Tissue Proteins/genetics,metabolism Regulatory Sequences, Nucleic Acid Repressor Proteins/genetics,metabolism Spinocerebellar Ataxias/genetics Trinucleotide Repeat Expansion
Chemicals
ATXN7 protein, human Ataxin-7 Atxn7 protein, mouse CCCTC-Binding Factor CTCF protein, human Ctcf protein, mouse DNA-Binding Proteins Nerve Tissue Proteins Repressor Proteins
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Libby Randell T
Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA, USA.
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
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1000257
Published
2008-11-00
Epub
2008-00-14
Pages
e1000257
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2573955
Subset
IM
Grants
NEI NIH HHS · EY14061 · United States
NIAMS NIH HHS · AR050741 · United States
NCI NIH HHS · R01 CA068360 · United States
NIA NIH HHS · T32 AG000057 · United States
NIAMS NIH HHS · AR4203 · United States
NIA NIH HHS · AG00057 · United States
NCI NIH HHS · CA68360 · United States
NEI NIH HHS · R01 EY014061 · United States
NIGMS NIH HHS · R01 GM059356 · United States
NIGMS NIH HHS · GM59356 · United States
External Links
PubMed source DOI: 10.1371/journal.pgen.1000257 PMC Full Text View journal details
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