Nuclear Structure and Gene Expression

描述（由申请人提供）：我们的计划项目是一个主题和操作集成的多学科方法，以实验方式解决功能上与转化和肿瘤细胞中的修饰转录控制相关的核组织组件。 我们的工作假设是，核结构的参数支持正常和肿瘤细胞的细胞生长和表型特性，通过促进染色体，基因和调控复合物的组织作为动态的，三维的细胞核内的微环境。在一个高度合作的环境中，这个项目有助于建立范式转变的见解：1）有丝分裂保留的转录因子在基因位点的表观遗传控制细胞命运; 2）要求保真度的核组织，以支持整合的调控途径和网络; 3）染色质结构和重塑乳腺上皮细胞形态的关系; 4）白血病和乳腺癌中的强制性核结构-功能关系;和5）调节蛋白亚核靶向对转移性乳腺肿瘤控制骨质溶解的贡献。在更新申请中，我们将从功能上定义新的维度，将核结构与基因表达以及核结构变化与肿瘤细胞异常生长联系起来的调控机制。我们的重点将是受损的亚核组织和组装的调节机制在核微环境中的转移性乳腺癌和白血病细胞的生物控制受到损害。将采用细胞、分子、生物化学、体内遗传、微观、基因组和蛋白质组学策略来解决介导核结构-基因表达相互关系的机制。该方案侧重于：癌细胞的亚核靶向和结构表观遗传学（项目1）;染色质重塑介导的基因调控与核组织和乳腺肿瘤发生参数的联系（项目2）;核微环境中转录复合物的组织介导转移性骨疾病（项目3）。

DESCRIPTION (provided by applicant): Our program project is a thematically and operationally integrated multidisciplinary approach to experimentally address components of nuclear organization that are functionally linked to modified transcriptional control in transformed and tumor cells. Our working hypothesis is that parameters of nuclear architecture support cell growth and phenotypic properties of normal and tumor cells by facilitating the organization of chromosomes, genes and regulatory complexes as dynamic, three-dimensional microenvironments within the nucleus. In a highly collaborative setting, this program project has been instrumental in establishing paradigm-shifting insights into: 1) mitotic retention of transcription factors at gene loci for epigenetic control of cell fate; 2) requirements for fidelity of nuclear organization to support integration of regulatory pathways and networks; 3) relationships of chromatin structure and remodeling to mammary epithelial cell morphology; 4) obligatory nuclear structure-function relations in leukemia and breast cancer; and 5) contributions of regulatory protein subnuclear targeting for control of osteolysis by metastatic breast tumors. In the renewal application we will functionally define novel dimensions to regulatory mechanisms that relate nuclear structure to gene expression and to changes in nuclear architecture to aberrant growth of tumor cells. Our emphasis will be on impaired subnuclear organization and assembly of regulatory machinery in nuclear microenvironments of metastatic breast cancer and leukemia cells in which biological control is compromised. Cellular, molecular, biochemical, in vivo genetic, microscopic, genomic and proteomic strategies will be pursued to address mechanisms mediating nuclear structure-gene expression interrelationships. The program focuses on: subnuclear targeting and architectural epigenetics in cancer cells (Project 1); linkage of chromatin remodeling-mediated gene regulation with parameters of nuclear organization and breast tumorigenesis (Project 2); and organization of transcriptional complexes in nuclear microenvironments to mediate metastatic bone disease (Project 3).