Subnuclear Targeting and Architectural Epigenetics in Cancer Cells

癌细胞的亚核靶向和结构表观遗传学

• 批准号: 8052324
• 负责人: Gary S. Stein
• 金额: $ 30.86万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052324
• 关键词: Acetylation; Acute Myelocytic Leukemia; Architecture; Biochemical; Biological; Breast Cancer Cell; Cell Fate Control; Cell Nucleus; Cell division; Cells; Chimeric Proteins; Chromatin; Chromatin Structure; Chromosomes; Chromosomes, Human, Pair 1; Collaborations; Commit; DNA Methylation; DNA Polymerase I; DNA Polymerase II; DNA Sequence; Dimensions; Environment; Epigenetic Process; Etiology; Event; Exhibits; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genomics; Histones; Instruction; Interphase; Link; Malignant Neoplasms; Mediating; Methods; Microscopy; Mitosis; Mitotic; Mitotic Chromosome; Modification; Molecular; Normal Cell; Nuclear; Nuclear Structure; Oncogenic; Phenotype; Post-Translational Protein Processing; Proteins; Proteomics; Regulation; Regulator Genes; Research Personnel; Role; Shapes; Signal Transduction; Somatic Cell; Structure; cancer cell; cancer stem cell; malignant breast neoplasm; metaplastic cell transformation; novel; programs; promoter; t(8; 21)(q22; q22); trafficking; transcription factor; tumorigenesis

Cancer cells exhibit alterations in parameters of nuclear architecture that control cell fate and compromise control of cell groyvth. Our Program has established new biological paradigms by showing that gene regulatory factors integrate cell signaling at chromatin microenvironments ('subnuclear foci') and support epigenetic mechanisms through association with mitotic chromosomes. In collaboration with other Program Project investigators. Project 1 will now establish new dimensions in gene regulation by defining perturbations in architecturally linked regulatory mechanisms during interphase and mitosis in AML and breast cancer cells. Our central hypothesis is that (i) subnuclear targeting of transcription factors to gene regulatory foci during interphase and (ii) the association of transcription factors wifh their target genes in mitotic chromosomes are fundamental to the retention of biological states of normal and cancer cells. Therefore, we will use IF microscopy, biochemical, genomic and proteomic approaches (i) to characterize modificafions in architectural epigenetics and molecular pathological consequences of expressing the translocation-related t(8;21) AML-ETO fusion protein (Aim 1), (ii) to analyze genes that are transcriptionally and spatially controlled by Runx2 in chromatin micro-environments ('subnuclear foci') during interphase in breast cancer ceils (Aim 2), and (iii) to examine Runx2 mediated architectural epigenetics in breast cancer cells by characterization of Runx2 and cognate gene regulatory factors that associate with mitotic chromosomes (Aim 3). By investigating the functional role of Runx2 in establishing chromatin micro- environments ('subnuclear foci') during interphase and architectural epigenetics in cancer cells during mitosis, we will challenge traditional biochemical views of gene regulation by defining the pathological linkages between modifications in nuclear architecture and gene expression that are fundamental to the molecular etiology of tumorigenesis. RELEVANCE (See instructions): Changes in the overall shape and structure ofthe nucleus are pathological hallmarks of cancer cells that are linked to cellular transformation. This study will use state-of-the-art methods to characterize how targeting of oncogenic transcription factors to specific subnuclear structures and mitotic chromosomes supports gene regulation as components of a novel epigenetic mechanism ('architectural epigenetics').

癌细胞表现出控制细胞命运和妥协的核结构参数的变化 控制细胞生长。我们的项目已经建立了新的生物学范例，通过展示基因 调节因子整合染色质微环境(“亚核焦点”)的细胞信号和支持 与有丝分裂染色体相关的表观遗传机制。与其他项目合作 项目调查员。项目1将在基因调控方面建立新的维度，通过定义 急性髓系白血病和急性髓细胞白血病间期和有丝分裂期间结构相关调节机制的扰动 乳腺癌细胞。我们的中心假设是(I)转录因子对基因的亚核靶向 间期的调控焦点和(Ii)转录因子与其靶基因的关系。 有丝分裂染色体是正常细胞和癌细胞保持生物状态的基础。 因此，我们将使用IF显微镜、生化、基因组和蛋白质组方法(I)来表征 建筑表观遗传学中的修饰和表达该基因的分子病理学后果 易位相关t(8；21)AML-ETO融合蛋白(目标1)，(Ii)分析转录水平的基因 和Runx2在染色质微环境(亚核焦点)中的空间控制 乳腺癌细胞(目标2)，以及(Iii)检测Runx2介导的乳腺癌的构造性表观遗传学 Runx2和与有丝分裂相关的同源基因调控因子对细胞的影响 染色体(目标3)。通过研究Runx2在建立染色质微结构中的功能作用 间期环境(‘亚核灶’)和癌细胞的构造性表观遗传学 有丝分裂，我们将挑战传统的生化基因调控的观点，通过定义病理 核结构的修饰和基因表达之间的联系是 肿瘤发生的分子病因学。 相关性(请参阅说明)： 细胞核整体形状和结构的变化是癌细胞的病理特征 与细胞转化有关。这项研究将使用最先进的方法来表征目标是如何 致癌转录因子对特定亚核结构和有丝分裂染色体的支持基因 调控是一种新的表观遗传学机制的组成部分(“建筑表观遗传学”)。