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

拟议的项目将汇集三个研究小组，使用互补的实验方法协同研究新发现的泰特酶的生理功能。泰特酶在基因表达调控中具有重要作用，并且似乎保护基因免于甲基化。在巴勒斯坦实验室的重点关注的癌症中，这些酶的活性降低被认为是导致超甲基化和异常基因表达的原因。然而，几乎没有人知道这些酶的作用和/或调节的差异机制。我们的试点研究表明，泰特酶在控制生殖的垂体促性腺激素的发育分化中起着重要作用;这是德国和以色列实验室分别在生理和分子水平上工作的主要焦点。这三个小组将在适当的细胞系和从转基因小鼠分离的原代细胞中对泰特的作用机制和分子调控进行详细研究。巴勒斯坦研究小组将研究乳腺癌样本中泰特表达与临床结果的相关性。德国研究小组将创造条件性基因敲除小鼠，这些小鼠缺乏垂体促性腺激素中特定的泰特酶的单独或组合，而巴勒斯坦研究小组将创造乳腺中特定的TET酶。这三个小组将相应地研究对生殖生理学、分子生物学和癌症发展的影响。通过这种方式，我们希望推进我们对基因调控这一新方面的作用的理解，同时在生殖疾病和癌症的背景下进一步开展翻译研究。

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.