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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Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
Chao, W
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Huynh, KD
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Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
Huynh, KD
;
Spencer, RJ
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Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
Spencer, RJ
;
Davidow, LS
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Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
Davidow, LS
;
Lee, JT
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Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
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CASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USACASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USA
Clemson, CM
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McNeil, JA
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CASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USACASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USA
McNeil, JA
;
Willard, HF
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CASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USACASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USA
Willard, HF
;
Lawrence, JB
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CASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USACASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USA
机构:
Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
Chao, W
;
Huynh, KD
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机构:
Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
Huynh, KD
;
Spencer, RJ
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机构:
Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
Spencer, RJ
;
Davidow, LS
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机构:
Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
Davidow, LS
;
Lee, JT
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机构:
Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USAHarvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA
机构:
CASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USACASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USA
Clemson, CM
;
McNeil, JA
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机构:
CASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USACASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USA
McNeil, JA
;
Willard, HF
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机构:
CASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USACASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USA
Willard, HF
;
Lawrence, JB
论文数: 0引用数: 0
h-index: 0
机构:
CASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USACASE WESTERN RESERVE UNIV, DEPT GENET, CTR HUMAN GENET, CLEVELAND, OH 44106 USA