DNA METHYLATION AND MAMMALIAN DEVELOPMENT

DNA 甲基化与哺乳动物发育

• 批准号: 6679493
• 负责人: EN LI
• 金额: $ 32.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6679493
• 关键词: DNA methylation; cell growth regulation; cell proliferation; developmental genetics; enzyme activity; enzyme structure; flow cytometry; fluorescent in situ hybridization; gene expression; gene targeting; genetically modified animals; genomic imprinting; laboratory mouse; mammalian embryology; methyltransferase; northern blottings; polymerase chain reaction; sex chromosomes; southern blotting

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.

描述(改编自研究人员摘要)：DNA甲基化是 对哺乳动物的发育至关重要，是一种关键的表观遗传机制，通过它 重要的发育过程，如基因组印记和X染色体 失活是受调控的。DNA甲基化在人类基因组中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 内源性病毒的感染和稳定沉默。DNA甲基化模式 在胚胎发育期间建立，并在体细胞组织中维持 在整个成年生活中。DNA甲基化模式的异常变化可导致 基因表达异常与疾病。为了了解DNA是如何 甲基化模式和基因表达谱在正常情况下受到调节 发展，重要的是要研究催化甲基化和 去甲基化反应。新生Dnmt3家族的鉴定 甲基转移酶为实验操作提供了许多可能性 这个DNA修饰系统。 该项目将解决一些基本问题，包括 从头开始甲基转移酶DNMT3a和3b的结构与功能关系 从头甲基化在细胞增殖、组织发育中的作用 分化、基因组印迹和X失活及其机制 DNA甲基化对基因表达的转录调控。遗传和 将采用生化方法研究DNMT3A和DNMT3A的功能 新甲基转移酶3B的正常发育及其调控机制 DNMT3a和3b的活性。DNMT3a和3b甲基转移酶的研究将 为基因表达的表观遗传调控提供新的见解 这将有助于理解DNA甲基化的异常变化 这种模式可能会导致ICF综合征和癌症等疾病。

项目成果

Structure and function of eukaryotic DNA methyltransferases.

• DOI: 10.1016/s0070-2153(04)60003-2
• 发表时间: 2004
• 期刊: Current topics in developmental biology
• 作者: Taiping Chen;E. Li

The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice.

• DOI: 10.1006/dbio.1999.9370
• 发表时间: 1999-09
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Jihwan Song;Suk P. Oh;H. Schrewe;Masatoshi Nomura;Hong Lei;Makiko Okano;Thomas Gridley;En Li

X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation.

• DOI: 10.1006/dbio.2000.9823
• 发表时间: 2000-09
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: T. Sado;M. Fenner;Seong‐Seng Tan;P. Tam;Toshihiro Shioda;En Li

Genetic analyses of DNA methyltransferase genes in mouse model system.

小鼠模型系统中DNA甲基转移酶基因的遗传分析。

• DOI: 10.1093/jn/132.8.2462s
• 发表时间: 2002
• 期刊: The Journal of nutrition
• 作者: Okano,Masaki;Li,En
• 通讯作者: Li,En

Regulation of imprinted X-chromosome inactivation in mice by Tsix.

Tsix 对小鼠印记 X 染色体失活的调节。

• DOI: 10.1242/dev.128.8.1275
• 发表时间: 2001
• 期刊: Development (Cambridge, England)
• 作者: Sado,T;Wang,Z;Sasaki,H;Li,E
• 通讯作者: Li,E