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，以实验方式解决核组织的组件，这些组件在功能上与转化细胞和肿瘤细胞中修饰的转录控制有关。 我们的工作假设是，核结构参数通过促进染色体、基因和调控复合体作为细胞核内动态的三维微环境的组织，支持正常细胞和肿瘤细胞的生长和表型特性。在高度协作的背景下，该计划项目在以下方面帮助建立了范式转换的见解：1)转录因子在基因位点的有丝分裂保持，用于表观遗传控制细胞命运；2)核组织的保真度要求，以支持调控途径和网络的整合；3)染色质结构和重塑与乳腺上皮细胞形态的关系；4)白血病和乳腺癌中必须的核结构-功能关系；以及5)调控蛋白亚核靶向对控制转移性乳腺肿瘤骨溶解的贡献。在更新应用中，我们将在功能上定义与核结构和基因表达相关的调控机制的新维度，以及与肿瘤细胞异常生长相关的核结构变化。我们的重点将放在转移性乳腺癌和白血病细胞的核微环境中受损的亚核组织和调控机制的组装，在这些微环境中，生物控制受到了损害。将采用细胞、分子、生化、体内遗传、显微、基因组和蛋白质组策略来解决核结构-基因表达相互关系的调节机制。该计划的重点是：癌细胞的亚核靶向和构造性表观遗传学(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)；以及核微环境中转录复合体的组织以介导转移性骨疾病(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).