Transmission and immunity: the importance of heterogeneity in the fight against malaria.

The complex relationship between transmission and parasite prevalence in humans is an important issue. Using a large dataset matching estimates of malaria transmission and Plasmodium falciparum prevalence in African children, a stimulating study published in Nature provides evidence that heterogeneity in susceptibility crucially determines the prevalence of infection. Moreover, it suggests that children who clear infections are not immune to new infections, irrespective of the amount of transmission. It is important to question the relevance of such results based on mathematical models when discussing host-parasite interactions, especially their implications for public health interventions.

[Epigenetics and cancer]. / Epigénétique et cancer.

The term epigenetics encompasses all the modifications that are stable across cell generations, but which do not imply any change in DNA sequence. Post-translational modifications of the histones and DNA methylation are the most studied types of epigenetic information due to their major impact on transcription. The link between epigenetics and cancer arises from the fact that epigenetic deregulations frequently participate in tumorigenesis by inactivation of tumour-suppressor genes. Since these deregulations are reversible, hopes of treatment rely on a better understanding of the maintenance mechanisms of the epigenetic information. Among the different pathways of transcription inhibition, DNA methylation is the simplest and one of the best characterized at the present time. Inhibitors of DNA methyltransferases are currently under clinical trials and already show promising results.

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.

The human enhancer blocker CTC-binding factor interacts with the transcription factor Kaiso.

CTC-binding factor (CTCF) is a DNA-binding protein of vertebrates that plays essential roles in regulating genome activity through its capacity to act as an enhancer blocker. We performed a yeast two-hybrid screen to identify protein partners of CTCF that could regulate its activity. Using full-length CTCF as bait we recovered Kaiso, a POZ-zinc finger transcription factor, as a specific binding partner. The interaction occurs through a C-terminal region of CTCF and the POZ domain of Kaiso. CTCF and Kaiso are co-expressed in many tissues, and CTCF was specifically co-immunoprecipitated by several Kaiso monoclonal antibodies from nuclear lysates. Kaiso is a bimodal transcription factor that recognizes methylated CpG dinucleotides or a conserved unmethylated sequence (TNGCAGGA, the Kaiso binding site). We identified one consensus unmethylated Kaiso binding site in close proximity to the CTCF binding site in the human 5' beta-globin insulator. We found, in an insulation assay, that the presence of this Kaiso binding site reduced the enhancer-blocking activity of CTCF. These data suggest that the Kaiso-CTCF interaction negatively regulates CTCF insulator activity.