Mechanisms of Genomic Imprinting

描述（由申请人提供）：DNA甲基化模式在发育过程中如何形成——甲基化和去甲基化如何在特定时间针对特定位点——尚不清楚。生殖细胞在消除从上一代遗传的男性和女性特异性标记后，根据性腺的性别建立甲基化印记。我们的主要假设是DNA胞嘧啶5-羟甲基化和染色质组成是印记周期的重要组成部分，参与生殖细胞的擦除和建立阶段以及体细胞的维持阶段。为了证明这一点，我们将全面分析生殖细胞和体细胞中特定印记基因的 DNA 甲基化、DNA 胞嘧啶羟甲基化和染色质。为了测试特定表观遗传修饰剂在印记周期中的作用，我们将在印记周期的擦除、建立和维持阶段从基因上扰乱这些功能。这些结果共同将有助于理解 DNA 甲基化、DNA 羟甲基化和染色质标记如何在生殖细胞的表观遗传重塑以及擦除、建立和维持基因组印记中相互协作。胚胎-胎儿生殖细胞发育过程中正确的整体表观遗传重塑和印记重置对于下一代和子孙后代的健康至关重要。

DESCRIPTION (provided by applicant): How DNA methylation patterns are shaped during development - how methylation and demethylation are targeted to specific loci at specific times - is not known. Germ cells establish methylation imprints depending on the sex of the gonad after erasing the male and female -specific marks inherited from the previous generation. Our main hypothesis is that DNA cytosine 5-hydroxymethylation and chromatin composition are important components of the imprint cycle, being involved in the erasure and establishment phases in germ cells and in the maintenance phase in the soma. To demonstrate this, we will analyze DNA methylation, DNA cytosine hydroxymethylation and chromatin globally and at specific imprinted genes in germ cells and somatic cells. To test the role of specific epigenetic modifiers in the cycle of imprinting, we will genetically perturb these functions during the erasure, establishment and maintenance phases of the imprinting cycle. These results collectively will help understand how DNA methylation, DNA hydroxymethylation and chromatin marks collaborate in the epigenetic remodeling of germ cells and in erasing, establishing and maintaining genomic imprints. Correct global epigenetic remodeling and imprint reseting during embryonic-fetal germ cell development is essential for the health of the next generation and for future generations.