Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation

Elena M. Pugacheva, Vijay Kumar Tiwari, Ziedulla Abdullaev, Alexander A. Vostrov, Patrick T. Flanagan, Wolfgang W. Quitschke, Dmitri I. Loukinov, Rolf Ohlsson, Victor V. Lobanenkov

Research output: Chapter in Book/Report/Conference proceedingChapter

81 Citations (Scopus)

Abstract

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.
Original languageEnglish
Title of host publicationHuman Molecular Genetics
Pages953-965
Number of pages13
DOIs
Publication statusPublished - 01 Apr 2005

Publication series

NameHuman Molecular Genetics
Volume14

Fingerprint

X Chromosome Inactivation
Point Mutation
X Chromosome
Mutation
Fingers
Deoxyribonuclease I
Placenta
Chromatin
Mammals
Alleles
Gene Expression
DNA
Proteins

Cite this

Pugacheva, E. M., Tiwari, V. K., Abdullaev, Z., Vostrov, A. A., Flanagan, P. T., Quitschke, W. W., ... Lobanenkov, V. V. (2005). Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. In Human Molecular Genetics (pp. 953-965). (Human Molecular Genetics; Vol. 14). https://doi.org/10.1093/hmg/ddi089
Pugacheva, Elena M. ; Tiwari, Vijay Kumar ; Abdullaev, Ziedulla ; Vostrov, Alexander A. ; Flanagan, Patrick T. ; Quitschke, Wolfgang W. ; Loukinov, Dmitri I. ; Ohlsson, Rolf ; Lobanenkov, Victor V. / Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. Human Molecular Genetics. 2005. pp. 953-965 (Human Molecular Genetics).
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abstract = "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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Pugacheva, EM, Tiwari, VK, Abdullaev, Z, Vostrov, AA, Flanagan, PT, Quitschke, WW, Loukinov, DI, Ohlsson, R & Lobanenkov, VV 2005, Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. in Human Molecular Genetics. Human Molecular Genetics, vol. 14, pp. 953-965. https://doi.org/10.1093/hmg/ddi089

Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. / Pugacheva, Elena M.; Tiwari, Vijay Kumar; Abdullaev, Ziedulla; Vostrov, Alexander A.; Flanagan, Patrick T.; Quitschke, Wolfgang W.; Loukinov, Dmitri I.; Ohlsson, Rolf; Lobanenkov, Victor V.

Human Molecular Genetics. 2005. p. 953-965 (Human Molecular Genetics; Vol. 14).

Research output: Chapter in Book/Report/Conference proceedingChapter

TY - CHAP

T1 - Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation

AU - Pugacheva, Elena M.

AU - Tiwari, Vijay Kumar

AU - Abdullaev, Ziedulla

AU - Vostrov, Alexander A.

AU - Flanagan, Patrick T.

AU - Quitschke, Wolfgang W.

AU - Loukinov, Dmitri I.

AU - Ohlsson, Rolf

AU - Lobanenkov, Victor V.

PY - 2005/4/1

Y1 - 2005/4/1

N2 - 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.

AB - 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.

UR - http://www.mendeley.com/research/familial-cases-point-mutations-xist-promoter-reveal-correlation-between-ctcf-binding-preemptive-choi

U2 - 10.1093/hmg/ddi089

DO - 10.1093/hmg/ddi089

M3 - Chapter

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SN - 0964-6906 (Print)\r0964-6906 (Linking)

T3 - Human Molecular Genetics

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BT - Human Molecular Genetics

ER -

Pugacheva EM, Tiwari VK, Abdullaev Z, Vostrov AA, Flanagan PT, Quitschke WW et al. Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. In Human Molecular Genetics. 2005. p. 953-965. (Human Molecular Genetics). https://doi.org/10.1093/hmg/ddi089