MECHANISM OF GENOMIC IMPRINTING DURING SPERMATOGENESIS

描述（改编自研究者的摘要）：基因组印记是 配子发生过程中某些基因被标记的过程 差异表达亲本等位基因。 统治的印记 等位基因特异性表达在父母的种系中建立 在配子发生过程中，父本赋予父本印记 在精子发生过程中，母体赋予了他的染色体 卵子发生过程中的母体印记。 该应用程序将重点关注 父系印记建立的分子基础 精子发生。 Prader-Willi (PWS) 和 Angelman 的分子分析 人类 15q11-13 的 (AS) 综合征已确定功能印记 中心（IC）并提供了对可能调节的机制的见解 配子发生过程中的印记。 IC内的两个子区域 15q11-13 中的印记基因簇控制初级父系和 多个基因的母体特异性印记。 IC 的 3 kb 子区域 （PWS IC）包括外显子 1 和印记的启动子区域 SNRPN 基因似乎在设定父系印记中起主要作用 在精子发生过程中。 该次区域的突变导致 PWS 防止在 15q11-13 基因上建立父系印记， 破坏精子发生过程中整个区域的印记。 一旦 主要的父亲特定印记设置在 PWS IC 中，该主要的 然后印记信号必须传输到每个印记基因 15q11-13 建立基因表达的父本模式。 既没有 主要印记或传输主要 IC 印记的机制 目前已知单个基因的信号。 该应用程序将 确定主要和基因特异性的性质和时间 小鼠 7C 号染色体 PWS/AS 同渗区的印记信号 在精子发生过程中。 小鼠不同阶段的细胞 将分离精子发生并检查差异 DNA 甲基化、DNase I 超敏感位点和 DNA-蛋白质相互作用 小鼠 7C 可能表明主要和基因特异性印记 信号。 了解印记的分子基础可能会导致 治疗已知涉及的遗传性疾病的治疗方法 印记。

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.