Functional role of TET-dependent DNA demethylation in reproduction and hormone-dependent cancers.

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The proposed project will bring together three research groups to investigate synergistically the physiological function of the newly discovered TET enzymes using complementary experimental approaches. TET enzymes have vital roles in gene expression regulation, and appear to protect genes from methylation. In hormone-dependent cancer, the focus of the Palestinian lab, reduced activity of these enzymes is suggested to be responsible for hypermethylation and aberrant gene expression. However, almost nothing is known about the differential mechanisms of action and/or regulation of these enzymes. Our pilot studies suggest that TET enzymes play a major role in developmental differentiation of the pituitary gonadotropes, which control reproduction; this is the main focus of the German and Israeli labs, working at physiological and molecular levels, respectively. The three groups will carry out detailed study on TET mechanisms of action and molecular regulation in appropriate cell lines and primary cells isolated from genetically modified mice. The Palestinian group will study breast cancer samples for correlation of TET expression and clinical outcome. The German group will create conditional knockout mice lacking individual or combinations of TET enzymes specifically in the pituitary gonadotropes and, with the Palestinian group, in the mammary gland. The three groups will examine the effects on reproductive physiology, molecular biology and cancer development, accordingly. In this way, we hope to advance our understanding of the role of this novel aspect of gene regulation, while furthering translational research in the context of reproductive disorders and cancer.