Tuesday 16 July 2019 16:00 – 17:00 A. Payatakes Seminar Room
” The role of Setdb1 in intestinal progenitor cells and in colorectal tumorigenesis”
Dr. Ioanna Peraki Institute of Molecular Biology and Biotechnology (IMBB)
Abstract
Setdb1 is a histone-3-lysine-9 methylase, which is highly expressed in embryonic-stem (ES) cells and in a variety of tumors including breast, skin, liver, colon and lung cancer. Setdb1 enzymatic activity contributes to the generation of a condensed, closed chromatin state and transcriptional repression. Previous studies have demonstrated that Setdb1 in ES cells is required for the suppression of a subset of genes encoding developmental regulators. In this way Setdb1 prevents uncontrolled differentiation, contributing to the mechanisms responsible for the maintenance of the pluripotent, stem cell phenotype. Setdb1 function in cancer is less well explored. While in many cases a correlation between Setdb1 expression and cancer phenotype is well established, evidence for a causative relationship is still missing. The current proposal is based on the hypothesis that similar to ES cells, Setdb1 may also repress differentiation specific regulators in adult somatic stem cells, like the intestinal Lgr5+ progenitor cells. The established role of Wnt signaling in both, intestinal progenitor cell maintenance and colorectal cancer, and the putative oncogenic function of Setdb1 in different organs, warrants parallel studies on the role of Setdb1 in progenitor cell maintenance and in colorectal cancer formation. We thus put forward the hypothesis that Setdb1deficiency may induce premature differentiation of Lgr5+ cells and derivative cancer stem cells, which may influence epithelium renewal or the growth characteristics of intestinal tumors.
To address these questions, we will conduct a study, which combines analyses of relevant mouse models with investigations of intestinal progenitor-derived organoid cultures. We expect this effort will not only decipher the role of Setdb1 in colorectal cancer but may also provide broader insights into the epigenetic mechanisms involved in the maintenanc