Human Molecular Genetics Advance Access originally published online on February 24, 2005
Human Molecular Genetics 2005 14(7):953-965; doi:10.1093/hmg/ddi089
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Published by Oxford University Press 2005.
Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation
,*1Molecular Pathology Section, Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA, 2Department of Development and Genetics, Uppsala University, Norbyvägen 18A, S-752 36 Uppsala, Sweden and 3Department of Psychiatry and Behavioral Science, State University of New York at Stony Brook, Stony Brook, New York 11794-81012, USA
* To whom correspondence should be addressed at: Molecular Pathology Section, LIP NIAID NIH, Twinbrook I, Room 1417, MSC-8152, 5640 Fisher Lane, Rockville, MD 20852, USA. Tel: +1 301 435 1690; Fax: +1 301 402 0077; Email: vlobanenkov{at}niaid.nih.gov
Received December 12, 2004; Revised February 4, 2005; Accepted February 14, 2005
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.
These authors contributed equally.
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