The role of ZRF1 in epigenetic control of transcription and tumor progression.

• Applicant: Dr. Martin Lange
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2009 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 131932885

The development of cancer in humans has been attributed to a combination of environmental factors such as exposure to carcinogens as well as genetic factors such as activation of oncogenes or inacti-vation of tumor suppressor genes. Altered expression of Polycomb proteins is observed in cancer. Several laboratories (including the one ofthe proposed supervisor) have contributed to the characteri-zation of the molecular mechanism of epigenetic gene silencing by Polycomb protein complexes (PRCs), which is initiated by methylation of histone H3K27 by Ezh2, a component of the PRC2 com-plex. Subsequent binding of PRC1 leads to the ubiquitination of histone 2A at lysine 119. The identifi-cation of ZRF1, the expression of which is often altered in cancer cells, as the first „reader" of ubiqui-tinated H2A now opens the possibility to investigate the downstream events of Polycomb-mediated gene repression in cancer (Richly et al., in review). We thus plan to investigate: (1) The chromatin occupancy of ZRF1 over the entire human genome. The new ultra-sequencing technology (lllumina) will allow not only to identify ZRF1 target genes, but also to unveil any additional regulative function of ZRF1 in the genome. (2) Furthermore, we propose to study how ZRF1 modulates promoter activity by identification of nuclear interactors of ZRF1 using a biochemical approach combined with mass-spectrometry. These data will provide a molecular understanding of ZRF1 nuclear function. (3) Finally, we aim to study the aberrant expression of ZRF1 in primary breast cancer samples as well as in leu-kemia blasts. We will also investigate whether ZRF1 interactors [identified in (2)] are also mis-regulated in cancer, and whether this correlates with tumor grade and with risk assessment.

• DFG Programme: Research Fellowships
• International Connection: Spain
• Host: Dr. Luciano di Croce