Chromosome pairing and condensins

我们工作的长期目标是了解不同的分子机制 染色体在身体上相互作用。在这项提案中，我们特别关注反式互动是如何产生负面影响的 受监管的。在许多物种的体细胞和减数分裂细胞中都发现了染色体的反式相互作用， 包括人类。目前关于染色体反式相互作用的一种观点认为，蛋白质将染色体带入 密切接近，并允许协调基因表达或染色体分离。例如, 染色体的反式相互作用对小鼠嗅觉受体基因的激活和 小鼠TH2 LCR基因座。在果蝇中也观察到了各种反式相互作用，无论是在体细胞 细胞(例如，转基因、反式沉默、多线染色体)和减数分裂细胞中广泛存在的 相互作用使同源染色体在整个长度上配对。减数分裂配对对于 染色体分离和表观遗传过程，如X失活、印迹和配对敏感 哺乳动物、植物和真菌中的减数分裂基因沉默。体细胞配对和减数分裂配对都可以通过 完全独立于DNA重组和修复蛋白的机制。染色体是如何 配对和不配对在任何有机体中基本上都是未知的。尽管有几种蛋白质被描述为 介导重组独立的减数分裂配对，目前尚不清楚是什么调节了体细胞 染色体配对。目前尚不清楚体细胞和减数分裂染色体配对在结构上是否相似。 或者它们是否受到相同因素的监管。我的实验室最近的研究表明，配对 体细胞二倍体染色体、多线染色体配对和减数分裂染色体配对都是 被凝集素II复合体拮抗。凝聚素是如何做到这一点的尚不清楚。然而，我们的观察 提供了对体细胞配对机制的第一次分子洞察，我们展示了一种新的染色体 凝聚素的反配对函数。凝聚素从细菌到人类都是保守的，因此 了解它们是如何调节染色体相互作用的，将揭示可能对 所有物种。这项建议建立在我们最近关于凝集素的工作基础上。首先，我们将使用遗传学来鉴定 与凝聚素合作调节多线染色体不配对的蛋白质。第二，我们将 确定凝聚素调节染色体配对敏感基因的机制(S) 在二倍体体细胞中表达。第三，我们将确定凝聚素的功能以及它们之间的相互作用 蛋白质，在调节减数分裂染色体配对中。

The long term goal of our work is to understand the molecular mechanisms through which different chromosomes physically interact. In this proposal we focus specifically on how trans-interactions are negatively regulated. Chromosomal trans-interactions have been seen in somatic cells and meiotic cells of many species, including human. A current view of chromosome trans-interactions posits that proteins bring chromosomes into intimate proximity and allow coordination of gene expression or chromosome segregation. For example, chromosome trans-interactions are important for gene activation in the mouse olfactory receptor gene and the mouse TH2 LCR locus. A variety of trans-interactions also have been observed in Drosophila, both in somatic cells (e.g.transvection, trans-silencing, polytene chromosomes) and in meiotic cells where extensive interactions pair homologous chromosomes throughout their lengths. Meiotic pairing is important for proper chromosome segregation and for epigenetic processes such as X-inactivation, imprinting, and pairing-sensitive meiotic gene silencing in mammals, plants and fungi. Both somatic and meiotic pairing can occur by mechanisms that are completely independent of DNA recombination and repair proteins. How chromosomes pair and unpair is largely unknown in any organism. Although a handful of proteins have been described to mediate recombination independent meiotic pairing, there is nothing known about what regulates somatic chromosome pairing. It is not known whether somatic and meiotic chromosome pairing are structurally similar or if they are regulated by the same factors. Work from my laboratory has recently demonstrated that pairing of somatic diploid chromosomes, polytene chromosome pairing and meiotic chromosome pairing are all antagonized by the condensin II complex. How condensins do this is unclear. However, our observations provide the first molecular insight into a somatic pairing mechanism, and we demonstrate a novel chromosome anti-pairing function for condensins. Condensins are conserved from bacteria to humans, therefore understanding how they regulate chromosome interactions will reveal basic functions likely to be important in all species. This proposal builds on our recent work on condensin. First, we will use genetics to identify the proteins that cooperate with condensins to regulate polytene chromosome unpairing. Second, we will determine the mechanism(s) through which condensins regulate chromosome pairing sensitive gene expression in diploid somatic cells. Third, we will determine the function of condensins, and their interacting proteins, in regulating meiotic chromosome pairing.