Developmental Control of Gene Expression and Nuclear Architecture by Cohesin

描述(申请人提供)：DNA在每个细胞的细胞核内高度组织。DNA环将沿着DNA线性维度相距很远的基因和调控元件聚集在一起，从而允许调控基因表达的调控相互作用。粘附素复合体是一种普遍表达的DNA环相互作用的介体。这种复合体在发育中起着关键作用；略微降低粘附素复合体亚单位或粘附素调节蛋白水平的突变会导致人类发育综合征，统称为粘附素病。这些综合征的特征是发育畸形和智力低下。尽管粘附素很重要，但它的确切作用和调节其功能的机制尚不清楚。拟议项目的目的是确定粘附素在发育过程中如何控制基因表达和核组织，并更好地了解粘附素功能丧失是如何影响发育的。这个项目将研究小鼠嗅觉感觉神经元的粘附素功能，这构成了一个具有良好特征和实验上易于处理的神经发育模型。对处于特定分化阶段的细胞进行的实验将确定由粘附素募集控制的发育调节的粘附素结合部位和DNA环状相互作用。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上的复合体来确定，特别是在这些细胞中。总之，这些实验将对粘附素在形成发育过程中的基因表达模式中的核心作用产生新的见解。

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.