Epigenetic Control and Genome Organization

总体概述 加里·斯坦和珍妮特·斯坦，项目总监 我们的计划项目是一个主题，实验和操作集成的多学科团队 一种方法来解决基因组组织的关键组成部分，这些组成部分在功能上与修饰的表观遗传有关 控制乳腺癌的基因表达。我们方案的主题重点和工作假设是 基因组组织和基因表达表观遗传控制协调地促进了 正常和癌细胞生长的生理调节，包括激素反应， 增殖和细胞特性。我们高度合作的研究团队建立了范式转变的见解 核组织的参数包括：1.有丝分裂基因书签的表型转录 细胞分裂时控制基因表达保真度的因素; 2.原子核的保真度与原子核 乳腺癌的组织学、转录因子定位和骨转移; 3.动态修改 乳腺癌细胞中更高阶的染色体间和染色体内相互作用; 4.单元协调控制 通过组织特异性转录因子的生长和表型; 5.内分泌治疗的表型分析 抗性和晚期乳腺癌细胞对选择性雌激素受体调节剂的应答;和6. 非编码RNA介导的侵袭性乳腺癌表型调节。 该应用程序捕捉了我们研究团队的科学进步、协同作用和动力，并利用 强大的新技术，用于编辑基因组，以超分辨率和真实的时间可视化细胞， 解码更高级的基因组结构我们将使用正常乳腺上皮细胞，亚型特异性和 内分泌耐药乳腺癌细胞模型的发现，然后验证关键发现，并检查潜在的 使用动物模型、公共数据库和患者肿瘤标本和类器官的临床相关性。 重点将在探索分子机制，整合多个层面的表观遗传控制 乳腺癌的基因组结构改变。这三个项目中的每一个都侧重于以下方面的一个独特方面： 表观遗传控制是基因表达保真度所需的，在乳腺癌中受到损害，包括： 有丝分裂基因书签在稳定正常乳腺上皮表型中的关键作用（项目1）; 布罗莫结构域染色质阅读器在内分泌治疗抵抗中的新功能（项目2）; 新的长非编码RNA MANCR对侵袭性乳腺癌基因组结构失调的影响 （项目3）。共享资源核心将支持生物信息学和生物统计学综合分析;标准化 实验设计;细胞、类器官和体内模型;以及资源认证，以确保科学的严谨性， 再现性一个行政核心将最大限度地实现科学和方案的一体化、优先次序的确定和 上级要员这一计划的影响将是基因组组织的多个层次的整合 和表观遗传控制，以了解乳腺癌中基因调控是如何被破坏的。

OVERALL PROGRAM SUMMARY Gary Stein and Janet Stein, Program Directors Our Program Project is a thematically, experimentally and operationally integrated multidisciplinary team approach to address key components of genome organization that are functionally linked to modified epigenetic control of gene expression in breast cancer. The thematic focus and working hypothesis of our Program is that genomic organization and epigenetic control of gene expression coordinately facilitate physiological regulation, including hormone responsiveness, of normal and cancer cell growth, proliferation and cell identity. Our highly collaborative research team established paradigm-shifting insights into parameters of nuclear organization that include: 1. Mitotic gene bookmarking by phenotypic transcription factors to control fidelity of gene expression as cells divide; 2. Relationships between fidelity of nuclear organization, transcription factor localization and metastasis of breast cancer to bone; 3. Dynamic modifications of higher-order inter- and intra-chromosomal interactions in breast cancer cells; 4. Coordinate control of cell growth and phenotype by tissue-specific transcription factors; 5. Epitranscriptomic profiling of endocrine therapy resistant and advanced breast cancer cells in response to selective estrogen receptor modulators; and 6. Noncoding RNA-mediated regulation of the aggressive breast cancer phenotype. This application captures the scientific progress, synergy and momentum of our research team and leverages powerful new technologies for editing the genome, visualizing cells at super resolution and in real time, and decoding higher-order genome organization. We will use normal mammary epithelial, subtype-specific and endocrine resistant breast cancer cell models for discovery, then validate key findings and examine potential clinical relevance using animal models, public databases and patient tumor specimens and organoids. Emphasis will be on exploring molecular mechanisms that integrate multiple dimensions of epigenetic control with modified genome organization in breast cancer. Each of the three projects focuses on a unique aspect of epigenetic control that is required for fidelity of gene expression and is compromised in breast cancer, including: the pivotal role of mitotic gene bookmarking in stabilizing the normal mammary epithelial phenotype (Project 1); novel functions of bromodomain chromatin readers in endocrine therapy resistance (Project 2); and contributions of the novel long noncoding RNA MANCR to deregulated genome organization in aggressive breast cancer (Project 3). A shared resource core will support integrated bioinformatics and biostatistics analyses; standardized experimental design; cell, organoid and in vivo models; and resource authentication to ensure scientific rigor and reproducibility. An administrative core will maximize scientific and programmatic integration, prioritization and oversight. The impact of this program will be the integration of multiple levels of genome organization and of epigenetic control to understand how gene regulation is disrupted in breast cancer.