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A Family of Human Zinc Finger Proteins That Bind Methylated DNA and Repress Transcription

Guillaume J. P. Filion,^1, Svetlana Zhenilo,^2, Sergey Salozhin,² Daisuke Yamada,¹ Egor Prokhortchouk,^2* and Pierre-Antoine Defossez^1*

Institut Curie, CNRS UMR218, Paris 75248, France,¹ Center "Bioengineering," Russian Academy of Sciences, Prospekt 60-let Oktyabrya 7-1, 117312 Moscow, Russia²

Received 8 July 2005/ Returned for modification 16 August 2005/ Accepted 12 October 2005

In vertebrates, densely methylated DNA is associated with inactive transcription. Actors in this process include proteins of the MBD family that can recognize methylated CpGs and repress transcription. Kaiso, a structurally unrelated protein, has also been shown to bind methylated CGCGs through its three Krüppel-like C₂H₂ zinc fingers. The human genome contains two uncharacterized proteins, ZBTB4 and ZBTB38, that contain Kaiso-like zinc fingers. We report that ZBTB4 and ZBTB38 bind methylated DNA in vitro and in vivo. Unlike Kaiso, they can bind single methylated CpGs. When transfected in mouse cells, the proteins colocalize with foci of heavily methylated satellite DNA and become delocalized upon loss of DNA methylation. Chromatin immunoprecipitation suggests that both of these proteins specifically bind to the methylated allele of the H19/Igf2 differentially methylated region. ZBTB4 and ZBTB38 repress the transcription of methylated templates in transfection assays. The two genes have distinct tissue-specific expression patterns, but both are highly expressed in the brain. Our results reveal the existence of a family of Kaiso-like proteins that bind methylated CpGs. Like proteins of the MBD family, they are able to repress transcription in a methyl-dependent manner, yet their tissue-specific expression pattern suggests nonoverlapping functions.

G.J.P.F. and S.Z. contributed equally to the work.

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