Subnuclear Targeting and Architectural Epigenetics in Cancer Cells

癌细胞表现出控制细胞命运和妥协的核结构参数的改变 控制细胞生长。我们的项目通过展示基因， 调节因子在染色质微环境（“亚核灶”）整合细胞信号传导， 通过与有丝分裂染色体相关的表观遗传机制。与其他方案合作 项目调查员。项目1现在将通过定义 AML间期和有丝分裂期间结构相关调控机制的扰动， 乳腺癌细胞我们的中心假设是：（i）转录因子的亚核靶向基因 调控焦点在间期和（ii）协会的转录因子wifh他们的靶基因， 有丝分裂染色体对于正常细胞和癌细胞的生物学状态的保持是基本的。 因此，我们将使用IF显微镜，生物化学，基因组学和蛋白质组学方法（i）来表征 修饰的建筑表观遗传学和分子病理后果的表达， 易位相关的t（8;21）AML-ETO融合蛋白（Aim 1），（ii）分析转录上 并且在染色质微环境（“亚核灶”）中由Runx 2在空间上控制。 乳腺癌细胞（目的2），和（iii）检查乳腺癌中Runx 2介导的结构表观遗传学 通过表征Runx 2和与有丝分裂相关的同源基因调控因子来鉴定细胞 染色体（目的3）。通过研究Runx 2在建立染色质微结构中的功能作用， 癌细胞的结构表观遗传学 有丝分裂，我们将挑战传统的生物化学观点的基因调控，通过定义病理 核结构和基因表达的修饰之间的联系，这是根本的， 肿瘤发生的分子病因学。 相关性（参见说明）： 细胞核整体形状和结构的变化是癌细胞的病理标志， 与细胞转化有关。这项研究将使用最先进的方法来表征如何靶向 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 调控作为一种新的表观遗传机制（“建筑表观遗传学”）的组成部分。

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').