Developmental Control of Gene Expression and Nuclear Architecture by Cohesin

描述（由申请人提供）：DNA在每个细胞的细胞核内高度组织化。DNA环将基因和沿着DNA的线性维度沿着的调控元件聚集在一起，允许调节基因表达的调控相互作用。黏连蛋白复合物是DNA环相互作用的普遍表达的介导物。这种复合物在发育中起着关键作用;轻微降低粘着蛋白复合物亚基或粘着蛋白调节蛋白水平的突变会导致人类发育综合征，统称为粘着蛋白病。这些综合征的特征是发育畸形和智力迟钝。尽管它的重要性，确切的作用，cohesin和调节其功能的机制是未知的。该项目的目的是确定在发育过程中cohesin如何控制基因表达和核组织，并更好地了解cohesin功能的丧失如何影响发育。本计画将探讨小鼠嗅觉感觉神经元中的黏连蛋白功能，此神经元为神经发育的良好表征及实验上易于处理的模型。在细胞分化的确定阶段的实验将确定发育调节的粘附素结合位点和DNA循环的相互作用，控制的粘附素招聘。在成熟的OSN中，粘附素在调节基因表达和核组织中的功能作用将通过删除粘附素或将粘附素加载到DNA上的复合物来确定，特别是在这些细胞中。总之，这些实验将产生新的洞察力的核心作用，粘着蛋白在模式基因表达的发展。

DESCRIPTION (provided by applicant): DNA is highly organized within the nucleus of each cell. DNA loops bring together genes and regulatory elements that are distant along the linear dimension of DNA, allowing regulatory interactions that modulate gene expression. The cohesin complex is a ubiquitously expressed mediator of DNA looping interactions. This complex has a critical role in development; mutations that slightly reduce the levels of cohesin complex subunits or cohesin regulatory proteins cause human developmental syndromes collectively dubbed cohesinopathies. These syndromes are characterized by developmental malformations and mental retardation. Despite its importance, the precise role of cohesin and the mechanisms that regulate its function are unknown. The purpose of the proposed project is to determine how cohesin controls gene expression and nuclear organization over the course of development and to better understand how loss of cohesin function affects development. This project will examine cohesin function in mouse olfactory sensory neurons, which constitute a well characterized and experimentally tractable model for neural development. Experiments on cells at defined stages of differentiation will identify developmentally regulated cohesin binding sites and DNA looping interactions that are controlled by cohesin recruitment. The functional role of cohesin in regulating gene expression and nuclear organization in mature OSNs will be determined by deleting cohesin, or the complex that loads cohesin onto DNA, specifically in these cells. Together these experiments will yield new insight into the central role of cohesin in patterning gene expression over development.