Exploring the mechanism and function of somatic homolog pairing

描述(申请人提供)：人类基因组由存储在细胞核内的每条染色体的两个副本组成。除了染色体的数量和结构外，染色体的位置和空间动态也受到严格控制。有大量证据表明，染色体之间的直接相互作用可以得到支持，甚至有助于几个基因的激活或抑制。我的研究将集中在一种特殊类型的相互作用上，即发生在母系和父系染色体之间的相互作用，称为同源配对。许多配对驱动的过程对人类发育至关重要，当出错时可能会导致疾病，结果从癌症到免疫系统受损、身体畸形和死亡。虽然人们已经了解了大量关于下游同源驱动过程中配对的需要，但几乎没有人知道同源染色体片段如何找到彼此，物理上对齐，然后在细胞内形成稳定的配对相互作用。这项建议的主要目标是确定和表征调节同源配对的因素和机制(目标1和2)。利用果蝇细胞中同源染色体沿其全长紧密配对的事实，我将筛选降低同源配对保真度的突变，然后描述已确定的遗传路径。最终，同源配对背后的基因特征将不仅揭示配对本身的机制，而且还将揭示配对调节的过程的机制，这些过程对人类发育和疾病具有影响。同源配对的过程与癌症研究特别相关，因为这些相互作用可以导致基因表达的戏剧性变化，因此可能有助于某些肿瘤的形成。最近在人类细胞中观察到了这一明显的证据，在肾嗜酸细胞瘤中，人类19号染色体Q臂的母系和父系拷贝沿其全长不适当地配对。这项研究提出了一种非常新的、令人兴奋的可能性，即同源基因配对状态与癌症直接相关。为了更好地了解染色体相互作用在癌症背景下的影响，因此我还将调查各种肿瘤细胞支持同源配对的能力(目标3)。如果在肾嗜酸细胞瘤以外观察到配对，这将表明染色体定位的变化，除了数字和结构异常外，还应被视为与肿瘤形成相关的事件，并成为治疗和预防癌症的新靶点。 公共卫生相关性：染色体间相互作用的问题显然与公共健康相关，因为配对可以导致转录的急剧变化，因此，在某些肿瘤的情况下，可能直接导致转移。事实上，异常的同源配对可能会增加有丝分裂交叉并导致杂合性丧失，这一过程长期以来一直被认为是包括癌症在内的许多疾病的根本原因。如果我们观察到肾嗜酸细胞瘤外转化细胞的配对，可能表明染色体定位的变化，除了数量和结构异常外，还应该被认为是与肿瘤发生有关的基因组事件。

DESCRIPTION (provided by applicant): The human genome is made up of two copies of each chromosome that are stored within the nucleus of cells. In addition to their number and structure, the position and spatial dynamics of chromosomes are under tight control. There is abundant evidence that direct interactions between chromosomes can be supported and even contribute to the activation or repression of several genes. My studies will focus on a particular type of interaction, that which occurs between maternal and paternal copies of chromosomes, known as homolog pairing. Many pairing-driven processes are essential for human development and can cause disease when gone awry, with outcomes ranging from cancers to compromised immune systems, physical deformities, and death. While a tremendous amount has been learned about the need of pairing on downstream homology- driven processes, almost nothing is known about how homologous chromosome segments find each other, physically align and then form stable pairing interactions within cells. The primary goal of this proposal is to identify and characterize the factors and mechanisms that mediate homolog pairing (Aims 1 and 2). Taking advantage of the fact that homologous chromosomes are intimately paired along their entire length in Drosophila cells, I will screen for mutations that decrease the fidelity of homolog pairing and then characterize the genetic pathways that are identified. Ultimately, the characterization of the genes underlying homolog pairing will not only shed light on the mechanism of pairing itself, but also the mechanisms of pairing-mediated processes that have implications for human development and disease. The process of homolog pairing is particularly relevant to cancer research, as these interactions can lead to dramatic changes in gene expression and may, therefore, contribute to the formation of some tumors. Striking evidence for this has recently been observed in human cells, wherein the maternal and paternal copies of the q arm of human Chromosome 19 inappropriately pair along its entire length in renal oncocytomas. This study raises the very new and exciting possibility that the state of homolog pairing is directly related to cancer. To better understand the impact of chromosomal interactions in the context of cancer, I will therefore also survey a wide variety of tumor cells for their ability to support homolog pairing (Aim 3). If pairing is observed outside of renal oncocytomas, it will indicate that changes in chromosome positioning, in addition to numerical and structural abnormalities, should be considered as an event associated with tumor formation and a new target for the treatment and prevention of cancer. PUBLIC HEALTH RELEVANCE: The issue of interchromosomal interactions is clearly relevant to public health, as pairing can lead to dramatic changes in transcription and may, therefore, directly contribute to metastasis in the case of some tumors. Indeed, aberrant homolog pairing may increase mitotic crossing over and lead to loss-of- heterozygosity, a process that has long been known to be the underlying cause for many diseases, including cancer. If we observe pairing in transformed cells outside of renal oncocytomas, it may indicate that changes in chromosome positioning, in addition to numerical and structural abnormalities, should be considered as a genomic event associated with tumorigenesis.