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Egor Prokhortchouk

Publications and source records attributed to Egor Prokhortchouk.

6 recordsLinked to original sources
PubMed2006

The X-linked methyl binding protein gene Kaiso is highly expressed in brain but is not mutated in Rett syndrome patients.

Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurological disorder, which affects mostly females. It is associated with mutations of the MECP2 gene, codifying for a methyl-CpG DNA binding protein of the MBDs family, sharing the common Methyl Binding Domain. MeCP2 binds single methylated CpG pair and brings transcriptional silencing to the substrate DNA templates. However, around 5-10% of clinically well defined RTT patients do not show any mutations in this gene. Several hypotheses have been postulated to clarify the remaining unexplained RTT cases. We pointed our attention on Kaiso gene. This gene is localized in the Xq23 region and codifies for a protein acting as a methyl-CpG binding protein by using three zinc-finger domains: for this reason it is not strictly related to the MBD family of proteins, even if it may repress transcription of methylated genes as well. To investigate the potential association of Kaiso disfunction with pathogenesis of Rett syndrome, we approached the analysis at two different levels. Primarily, we performed an itemized murine brain expression analysis of Kaiso gene. Expression data and localization made it an excellent candidate as additional causative gene for MECP2 negative, classical RTT patients. On the bases of this data a detailed mutational analysis of 44 patients from Spanish, UK, and Italian archives has been performed to the coding region of Kaiso. No mutation was found while a very frequent polymorphism was identified and characterized. Our study suggests that this gene is not implicated in the RTT molecular pathogenesis, but additional analyses are needed to exclude it as causative gene for X-linked mental retardation disorders.

Animals↗
PubMed2006

A family of human zinc finger proteins that bind methylated DNA and repress transcription.

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.

Amino Acid Sequence↗
PubMed2006

Kaiso-deficient mice show resistance to intestinal cancer.

Kaiso is a BTB domain protein that associates with the signaling molecule p120-catenin and binds to the methylated sequence mCGmCG or the nonmethylated sequence CTGCNA to modulate transcription. In Xenopus laevis, xKaiso deficiency leads to embryonic death accompanied by premature gene activation in blastulae and upregulation of the xWnt11 gene. Kaiso has also been proposed to play an essential role in mammalian synapse-specific transcription. We disrupted the Kaiso gene in mice to assess its role in mammalian development. Kaiso-null mice were viable and fertile, with no detectable abnormalities of development or gene expression. However, when crossed with tumor-susceptible Apc(Min/+) mice, Kaiso-null mice showed a delayed onset of intestinal tumorigenesis. Kaiso was found to be upregulated in murine intestinal tumors and is expressed in human colon cancers. Our data suggest that Kaiso plays a role in intestinal cancer and may therefore represent a potential target for therapeutic intervention.

Animals↗
PubMed2004

Kaiso is a genome-wide repressor of transcription that is essential for amphibian development.

DNA methylation in animals is thought to repress transcription via methyl-CpG specific binding proteins, which recruit enzymatic machinery promoting the formation of inactive chromatin at targeted loci. Loss of DNA methylation can result in the activation of normally silent genes during mouse and amphibian development. Paradoxically, global changes in gene expression have not been observed in mice that are null for the methyl-CpG specific repressors MeCP2, MBD1 or MBD2. Here, we demonstrate that xKaiso, a novel methyl-CpG specific repressor protein, is required to maintain transcription silencing during early Xenopus laevis development. In the absence of xKaiso function, premature zygotic gene expression occurs before the mid-blastula transition (MBT). Subsequent phenotypes (developmental arrest and apoptosis) strongly resemble those observed for hypomethylated embryos. Injection of wild-type human kaiso mRNA can rescue the phenotype and associated gene expression changes of xKaiso-depleted embryos. Our results, including gene expression profiling, are consistent with an essential role for xKaiso as a global repressor of methylated genes during early vertebrate development.

Animals↗