Splicing regulation in meiosis: characterising the role of a conserved RNA binding protein

目前基因表达分析的趋势是多学科的，严重依赖于分子分析和数据驱动的生物学。在这个项目中，学生将接受这两方面的专家的培训，在全球“组学”水平上分析RNA加工模式，并对关键的个人目标进行详细的跟踪。分子生物学将由纽卡斯尔集团(纽卡斯尔大学遗传医学研究所)教授。生物信息学将由Durham小组(Durham大学生物系Sushma Grellscheid博士)教授。不孕不育影响了许多夫妇，但导致不孕不育的原因通常不清楚。该项目将分析一种RNA结合蛋白，该蛋白已被发现在不育男性中发生突变或缺失，但到目前为止人们对此知之甚少。该项目将包括世界级的分子生物学和生物信息学培训，这将使学生在就业市场上处于有利地位。减数分裂是产生精子和卵子的特殊细胞分裂程序。这个项目将建立在最近获得BBSRC希望全面分析只在减数分裂中表达并与男性不育有关的RNA结合蛋白所产生的资源的基础上。我们利用野生型和基因敲除小鼠的RNAseq发现，这种RNA结合蛋白控制着雄性减数分裂过程中的核RNA加工。最令人惊讶的是，这包括防止内含子区域被错误地包括在mRNAs中，这会导致减数分裂转录组的中毒。目前尚不清楚hnRNP GT是如何发挥作用的。这个博士项目将检验这样的假设，即这种RNA结合蛋白通过直接RNA相互作用或通过与其他剪接调节因子相互作用来控制这些序列的剪接。这一点很重要，因为含有这种敲除基因的小鼠阻止了精子在减数分裂中的发育，并导致不育。

Current trends in gene expression analyses are multidisciplinary, and lean heavily on both molecular analyses and data driven biology. In this project the student will be trained by experts in both, to analyse RNA processing patterns at a global "-omics" level, along with detailed follow up of key individual targets. The molecular biology will be taught by the Newcastle group (Institute of Genetic Medicine, Newcastle University). The bioinformatics will be taught by the Durham group (Dr Sushma Grellscheid, Department of Biology, Durham University). Infertility affects many couples, but the reasons causing it are usually unknown. This project will analyse an RNA binding protein that has been identified as mutated or deleted in infertile men, yet is so far very poorly understood. This project will include world class training in both molecular biology and bioinformatics which will place the student in a strong place in the jobs market. Meiosis is the specialised cell division programme that makes sperm and eggs. This project will build on resources generated by a recently awarded BBSRC want to comprehensively analyse an RNA binding protein that is expressed only in meiosis and implicated in male infertility. We have discovered using RNAseq of wild type and knockout mice that this RNA binding protein controls nuclear RNA processing during male meiosis. Most surprisingly, this includes preventing regions of intron being mistakenly included into mRNAs which leads to poisoning of the meiotic transcriptome. It is not known how hnRNP GT functions. This PhD project will test the hypothesis that this RNA binding protein controls splicing of these sequences either by direct RNA interactions, or by interacting with other splicing regulators. This is important, as mice containing this knockout arrest sperm development in meiosis and are infertile.