Nuclear Structure and Gene Expression

我们的项目是一个综合的、多学科的团队方法，通过实验解决与转化细胞和肿瘤细胞中修饰的转录控制功能相关的核组织组成部分。我们的工作假设是，核结构参数通过促进染色体、染色质、基因、转录物和调控复合物在核结构的动态三维背景下的组织，支持正常细胞和肿瘤细胞的生长和表型特性。在一个高度协作的环境中，这个项目在建立核组织的多个组成部分对基因调控的贡献方面发挥了重要作用。我们对转录因子的核内转运、染色质重塑、染色体分离、核基质的结构和功能特性以及功能性核结构域有了深入的了解。在更新应用中，我们将进一步定义介导核结构-基因表达相互关系的机制，并将核形态的变化与肿瘤细胞的异常生长联系起来。重点是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基因调控机制的组装，这与生物控制受损有关。我们将继续结合细胞、生化、遗传和分子方法以及体内和体外模型系统来研究：1)核结构整合生理调控信号的机制，这些信号汇聚在一起支持基因表达；2)染色质重塑机制，使启动子元件接近转录因子和协调节蛋白；3)中心体组织与有丝分裂装置组装改变、染色体分离、核结构/功能和非整倍体有关；4)支持有丝分裂后转录的调控复合物的有丝分裂分布；5)组织特异性转录因子的核内转运与体内转移性乳腺癌细胞的转化、白血病发生和溶骨活性有关。

Our program project is an integrated, multidisciplinary team 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 structure support cell growth and phenotypic properties of normal and tumor cells by facilitating the organization of chromosomes, chromatin, genes, transcripts and regulatory complexes within the dynamic three-dimensional context of nuclear architecture. In a highly collaborative setting, this Program Project has been instrumental in establishing the contributions of multiple components of nuclear organization to gene regulation. We have advanced understanding of intranuclear trafficking of transcription factors, chromatin remodeling, chromosome segregation, structural and functional properties of the nuclear matrix, and functional nuclear domains. In the renewal application we will further define mechanisms that mediate nuclear structure-gene expression interrelationships and will relate changes in nuclear morphology to aberrant growth of tumor cells. Emphasis is on impaired subnuclear organization and assembly of gene regulatory machinery in nuclear microenvironments of metastatic breast cancer and leukemia cells that are associated with compromised biological control. We will continue to combine cellular, biochemical, genetic, and molecular approaches together with in vivo and in vitro model systems to investigate: 1) Mechanisms by which nuclear structure integrates physiological regulatory signals that converge to support gene expression; 2) chromatin remodeling mechanisms that render promoter elements accessible to transcription factors and coregulatory proteins; 3) centrosome organization in relation to altered assembly of the mitotic apparatus, chromosome segregation, nuclear structure/function, and aneuploidy; 4) mitotic distribution of regulatory complexes to support post-mitotic transcription; 5) perturbed intranuclear trafficking of tissue-specific transcription factors with transformation, leukemogenesis and osteolytic activity of metastatic breast cancer cells in vivo. Lay Summary: This program will continue to study fundamental structural properties of the cell nucleus that support biological control and are disrupted in leukemia and metastatic breast cancer. We will gain insight into components of nuclear organization that can be targeted for innovative cancer therapies.