Comparative analysis of Su(var) chromatin regulators in Drosophila and the mouse

异染色质在保护基因组完整性、维持细胞身份和稳定基因表达程序方面具有重要功能。在过去的15年中，一些涉及异染色质形成和维持的表观遗传因素已经被描述。特别是，对果蝇PEV（位置效应变异）的Su（var）突变的筛选已被证明有助于鉴定核心异染色质成分，其中大多数在高等真核生物中是保守的。尽管取得了这些重大进展，但值得注意的是，大约100个Su（var）基因座中只有25%被分子定义，其余未知基因座估计编码了大约70个新的异染色质调节因子。在这里，我们建议使用全基因组测序方法来快速定位在等基因果蝇菌株中产生的新的Su（var）突变。该分析预计将导致鉴定约50个新的SU（VAR）因素。果蝇和小鼠的功能分析将集中在选定的保守的Su（var）基因上，并将研究它们在全基因组基因沉默和异染色质形成中的分子作用。提出的研究计划将为果蝇和哺乳动物染色质分配的分子基础和异染色质调控的保守性方面提供重要的新见解。

Heterochromatin has important functions in protecting genome integrity, maintaining cell identity and stabilizing gene expression programs. During the last 15 years several epigenetic factors involved in heterochromatin formation and maintenance have been described. In particular, screens for Su(var) mutations of PEV (position effect variegation) in Drosophila have proven instrumental in identifying core heterochromatin components, most of which are conserved in higher eukaryotes. Despite these significant advances, it is important to note that only ~25% of the about 100 Su(var) loci have been molecularly defined, with the remaining unknown loci estimated to encode for approximately 70 novel heterochromatin regulators. Here, we propose to use a genome-wide sequencing approach to rapidly map novel Su(var) mutations that were generated in isogenic Drosophila strains. This analysis is expected to result in the identification of about 50 novel SU(VAR) factors. Functional analysis in Drosophila and mouse will focus on selected conserved Su(var) genes and will address their molecular roles in genome-wide gene silencing and heterochromatin formation. The proposed research plan will provide significant new insights into the molecular basis of chromatin partitioning and conserved aspects of heterochromatin regulation in Drosophila and mammals.