DNA METHYLATION AND MAMMALIAN DEVELOPMENT

描述（改编自研究者摘要）：DNA甲基化是 是哺乳动物发育所必需的，并且是一种关键的表观遗传机制， 重要的发育过程，如基因组印记和X染色体 失活受到调控。DNA甲基化起着至关重要的作用， 基因表达的发育调控，逆转录病毒的抑制 感染和内源性病毒的稳定沉默。DNA甲基化模式 在胚胎发育过程中建立并在体细胞组织中维持 在成年生活中。DNA甲基化模式的异常变化可导致 异常基因表达和疾病。为了了解DNA 甲基化模式，因此基因表达谱在正常 因此，研究催化甲基化的酶和 去甲基化反应Dnmt 3家族的鉴定 甲基转移酶为实验操作开辟了许多可能性 这个DNA修饰系统 该项目将解决一些基本问题，包括 从头甲基转移酶Dnmt 3a和3b结构-功能关系， 从头甲基化在细胞增殖、组织 分化、基因组印记和X染色体失活，以及 通过DNA甲基化的基因表达的转录调节。遗传和 将采用生物化学方法研究Dnmt 3a的功能， 3b在正常发育中的作用及从头甲基转移酶的调控机制 Dnmt 3a和3b的活性。Dnmt 3a和3b甲基转移酶的研究将 提供了新的见解表观遗传调控的基因表达， 这将有助于了解DNA甲基化的异常变化 这些模式可能导致ICF综合征和癌症等疾病。

DESCRIPTION (Adapted from investigator's abstract): DNA methylation is essential for mammalian development and is a key epigenetic mechanism by which important developmental processes such as genomic imprinting and X chromosome inactivation are regulated. DNA methylation plays a crucial role in developmental regulation of gene expression, suppression of retrovirus infection and stable silencing of endogenous viruses. DNA methylation patterns are established during embryonic development and maintained in somatic tissues throughout adult life. Aberrant changes of DNA methylation patterns can lead to abnormal gene expression and diseases. In order to understand how DNA methylation patterns and thus gene expression profiles are regulated in normal development, it is important to study the enzymes that catalyze methylation and demethylation reactions. The identification of the Dnmt3 family of de novo methyltransferases opens many possibilities for experimental manipulation of this DNA modification system. This project will address a number of fundamental issues including the structure-function relationship of de novo methyltransferases Dnmt3a and 3b, the function of de novo methylation in cell proliferation, tissue differentiation, genomic imprinting and X inactivation, and the mechanism of transcriptional regulation of gene expression by DNA methylation. Genetic and biochemical approaches will be taken to investigate the functions of Dnmt3a and 3b in normal development and regulatory mechanisms of de novo methytransferase activities of Dnmt3a and 3b. Studies of Dnmt3a and 3b methyltransferases will provide new insights into epigenetic regulation of gene expression in development and will help understand how abnormal changes of DNA methylation patterns may cause diseases such as ICF syndrome and cancer.