The interaction of xKaiso with xTcf3: a revised model for integration of epigenetic and Wnt signalling pathways.
We demonstrate that a direct interaction between the methyl-CpG-dependent transcription repressor Kaiso and xTcf3, a transducer of the Wnt signalling pathway, results in their mutual disengagement from their respective DNA-binding sites. Thus, the transcription functions of xTcf3 can be inhibited by overexpression of Kaiso in cell lines and Xenopus embryos. The interaction of Kaiso with xTcf3 is highly conserved and is dependent on its zinc-finger domains (ZF1-3) and the corresponding HMG DNA-binding domain of TCF3/4 factors. Our data rule out a model suggesting that xKaiso is a direct repressor of Wnt signalling target genes in early Xenopus development via binding to promoter-proximal CTGCNA sequences as part of a xTcf3 repressor complex. Instead, we propose that mutual inhibition by Kaiso/TCF3 of their DNA-binding functions may be important in developmental or cancer contexts and acts as a regulatory node that integrates epigenetic and Wnt signalling pathways.
Ruzov
Alexey
A
Human Genetics Unit, MRC, Western General Hospital, Edinburgh, UK.
Hackett
Jamie A
JA
Prokhortchouk
Anna
A
Reddington
James P
JP
Madej
Monika J
MJ
Dunican
Donncha S
DS
Prokhortchouk
Egor
E
Pennings
Sari
S
Meehan
Richard R
RR
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058125:Transcription Factor 7-Like 1 Protein; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*
D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein; D051153:Wnt Proteins; D029867:Xenopus Proteins; C451401:ZBTB33 protein, Xenopus; D004247:DNA