MECHANISM OF GENOMIC IMPRINTING DURING SPERMATOGENESIS

精子发生过程中的基因组印记机制

• 批准号: 2889510
• 负责人: THOMAS P YANG
• 金额: $ 24.8万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889510
• 关键词: DNA footprinting; DNA methylation; DNA replication; Prader Willi syndrome; alleles; chromosome disorders; deoxyribonuclease I; developmental genetics; gel electrophoresis; gene expression; gene mutation; genetic mapping; genomic imprinting; happy puppet syndrome; laboratory mouse; molecular genetics; nucleic acid sequence; restriction endonucleases; restriction fragment length polymorphism; restriction mapping; southern blotting; spermatogenesis

DESCRIPTION (Adapted from investigator's abstract): Genomic imprinting is the process by which certain genes are marked during gametogenesis to differentially express the parental alleles. The imprints that govern allele-specific expression are established in the germline of the parents during gametogenesis, such that the male parent confers a paternal imprint to his chromosomes during spermatogenesis, and the female parent confers a maternal imprint during oogenesis. This application will focus on the molecular basis for establishment of the paternal imprint during spermatogenesis. Molecular analysis of the Prader-Willi (PWS) and Angelman (AS) syndromes in human 15q11-13 has identified a functional imprinting center (IC) and provided insight into the mechanisms that may regulate imprinting during gametogenesis. Two subregions of the IC within the cluster of imprinted genes in 15q11-13 control the primary paternal- and maternal-specific imprinting of multiple genes. A 3 kb subregion of the IC (the PWS IC) that includes exon 1 and the promoter region of the imprinted SNRPN gene appears to play the primary role in setting the paternal imprint during spermatogenesis. Mutations in this subregion lead to PWS by preventing the establishment of a paternal imprint on genes in 15q11-13 and disrupting imprinting throughout this region in spermatogenesis. Once the primary paternal-specific imprint is set in the PWS IC, this primary imprinting signal must then be transmitted to each imprinted gene in 15q11-13 to establish the paternal pattern of gene expression. Neither the primary imprint nor the mechanism for transmitting the primary IC imprint signal to individual genes are currently known. This application will determine the nature and timing of both the primary and gene-specific imprinting signals in the PWS/AS syntonic region of mouse chromosome 7C during spermatogenesis. Cells from different stages of mouse spermatogenesis will be isolated and examined for differential DNA methylation, DNase I hypersensitive sites, and DNA-protein interactions in mouse 7C that may be indicative of the primary and gene-specific imprinting signals. Understanding the molecular basis of imprinting may lead to therapeutic approaches for treating genetic disorders known to involve imprinting.

描述（根据研究者的摘要进行了改编）：基因组印记是 在配配过程中标记某些基因的过程 差异表达父母等位基因。 管理的烙印 等位基因特定的表达是在父母的种系中建立的 在配子发生过程中，男性父母赋予父亲的烙印 在精子发生过程中，他的染色体和女性父母同意 卵子发生过程中的母体烙印。 该应用程序将重点放在 在建立父亲烙印期间的分子基础 精子发生。 Prader-Willi（PWS）和Angelman的分子分析 （AS）人类15q11-13中的综合征已确定了功能印记 中心（IC），并洞悉可能调节的机制 配子发生过程中的烙印。 IC的两个子区域 15q11-13中的烙印基因簇控制了主要的父亲和 多个基因的母体特异性印迹。 IC的3 kb子区域 （PWS IC）包括外显子1和印迹的启动子区域 SNRPN基因似乎在设置父亲烙印方面起着主要作用 在精子发生期间。 该子区域的突变导致PWS 防止在15q11-13和 在精子发生中破坏整个地区的印迹。 一旦 PWS IC中设置了主要的父亲特异性印记 然后必须将烙印信号传输到每个印迹基因中 15q11-13建立基因表达的父亲模式。 也不是 主要烙印或传输主要IC烙印的机制 目前已知向单个基因的信号。 此应用程序将 确定主要和基因特异性的性质和时机 PWS/作为小鼠染色体7C的同步区域中的烙印信号 在精子发生期间。 小鼠不同阶段的细胞 精子发生将分离并检查差异DNA 甲基化，DNase I超敏位点和DNA-蛋白质相互作用 鼠标7C可能指示主要和基因特异性印记 信号。 了解印迹的分子基础可能导致 治疗已知的遗传疾病的治疗方法 烙印。