Epigenetic Control and Genome Organization

总体计划摘要 项目总监加里·斯坦和珍妮特·斯坦 我们的计划项目是一个主题、实验和操作相结合的多学科团队 解决基因组组织中在功能上与修饰的表观遗传学相关的关键组件的方法 乳腺癌中基因表达的调控。我们计划的主题重点和工作假设是 基因组组织和基因表达的表观遗传控制协同促进 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。我们高度协作的研究团队建立了转变范式的见解 核组织参数包括：1.通过表型转录进行有丝分裂基因书签 控制细胞分裂时基因表达保真度的因素；2.核保真度之间的关系 乳腺癌的组织、转录因子定位和骨转移；3.动态修饰 乳腺癌细胞中染色体间和染色体内的高级相互作用；4.细胞的协调控制 组织特异性转录因子的生长和表型；5.内分泌治疗的表观转录图谱 耐药和晚期乳腺癌细胞对选择性雌激素受体调节剂的反应； 非编码RNA介导的侵袭性乳腺癌表型的调节。 这一应用程序捕捉到了我们研究团队的科学进步、协同作用和势头，并利用 强大的新技术，用于编辑基因组，以超分辨率和实时显示细胞，以及 破译更高级的基因组组织。我们将使用正常的乳腺上皮，亚型特异性和 发现内分泌耐药的乳腺癌细胞模型，然后验证关键发现并检查潜力 使用动物模型、公共数据库和患者肿瘤标本和器官的临床相关性。 重点将放在探索整合多维表观遗传控制的分子机制上 乳腺癌的基因组结构发生了改变。这三个项目中的每个项目都侧重于 基因表达保真度所需的表观遗传控制，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)； 溴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)；以及贡献 侵袭性乳腺癌中新的长非编码RNA MANCR对基因组组织失控的影响 (项目3)。共享资源核心将支持综合生物信息学和生物统计分析；标准化 实验设计；细胞、有机体和活体模型；以及资源认证，以确保科学严谨和 再现性。行政核心将最大限度地实现科学和方案一体化、确定优先次序和 疏忽。该计划的影响将是多个层面的基因组组织的整合 以及表观遗传控制，以了解乳腺癌的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.