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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2005-3-22
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pubmed:abstractText |
The choice mechanisms that determine the future inactive X chromosome in somatic cells of female mammals involve the regulated expression of the XIST gene. A familial C(-43)G mutation in the XIST promoter results in skewing of X chromosome inactivation (XCI) towards the inactive X chromosome of heterozygous females, whereas a C(-43)A mutation found primarily in the active X chromosome results in the opposite skewing pattern. Both mutations point to the existence of a factor that might be responsible for the skewed patterns. Here we identify this factor as CTCF, a conserved protein with a 11 Zn-finger (ZF) domain that can mediate multiple sequence-specificity and interactions between DNA-bound CTCF molecules. We show that mouse and human Xist/XIST promoters contain one homologous CTCF-binding sequence with the matching dG-contacts, which in the human XIST include the -43 position within the DNase I footprint of CTCF. While the C(-43)A mutation abrogates CTCF binding, the C(-43)G mutation results in a dramatic increase in CTCF-binding efficiency by altering ZF-usage mode required for recognition of the altered dG-contacts of the mutant site. Thus, the skewing effect of the two -43C mutations correlates with their effects on CTCF binding. Finally, CTCF interacts with the XIST/Xist promoter only in female human and mouse cells. The interpretation that this reflected a preferential interaction with the promoter of the active Xist allele was confirmed in mouse fetal placenta. These observations are in keeping with the possibility that the choice of X chromosome inactivation reflects stabilization of a higher order chromatin conformation impinging on the CTCF-XIST promoter complex.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0964-6906
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
14
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
953-65
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:15731119-Alleles,
pubmed-meshheading:15731119-Animals,
pubmed-meshheading:15731119-Base Sequence,
pubmed-meshheading:15731119-Cell Nucleus,
pubmed-meshheading:15731119-Chromatin,
pubmed-meshheading:15731119-Chromatin Immunoprecipitation,
pubmed-meshheading:15731119-Chromosomes, Human, X,
pubmed-meshheading:15731119-DNA Methylation,
pubmed-meshheading:15731119-DNA-Binding Proteins,
pubmed-meshheading:15731119-Deoxyribonuclease I,
pubmed-meshheading:15731119-Dosage Compensation, Genetic,
pubmed-meshheading:15731119-Family Health,
pubmed-meshheading:15731119-Female,
pubmed-meshheading:15731119-Heterozygote,
pubmed-meshheading:15731119-Humans,
pubmed-meshheading:15731119-Immunoprecipitation,
pubmed-meshheading:15731119-Male,
pubmed-meshheading:15731119-Mice,
pubmed-meshheading:15731119-Models, Genetic,
pubmed-meshheading:15731119-Molecular Sequence Data,
pubmed-meshheading:15731119-Mutation,
pubmed-meshheading:15731119-Plasmids,
pubmed-meshheading:15731119-Point Mutation,
pubmed-meshheading:15731119-Promoter Regions, Genetic,
pubmed-meshheading:15731119-Protein Binding,
pubmed-meshheading:15731119-Protein Biosynthesis,
pubmed-meshheading:15731119-Protein Conformation,
pubmed-meshheading:15731119-Protein Structure, Tertiary,
pubmed-meshheading:15731119-RNA, Untranslated,
pubmed-meshheading:15731119-Repressor Proteins,
pubmed-meshheading:15731119-Sequence Homology, Nucleic Acid,
pubmed-meshheading:15731119-Sex Factors,
pubmed-meshheading:15731119-Transcription, Genetic,
pubmed-meshheading:15731119-Zinc Fingers
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pubmed:year |
2005
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pubmed:articleTitle |
Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation.
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pubmed:affiliation |
Molecular Pathology Section, Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5640 Fishers Lane, Twinbrook I Rm. 1417, Rockville, MD 20852, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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