Epigenetic Control and Genome Organization

表观遗传控制和基因组组织

基本信息

批准号：
10380069
负责人：
Gary S. Stein
金额：
$ 173.49万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380069
关键词：
ATP phosphohydrolase Address Animal Model Architecture Biochemical Bioinformatics Biological Biometry Breast Cancer Cell Breast Cancer Patient Breast cancer metastasis Bromodomain Cancer Cell Growth Carcinoma Cell model Cells Chromatin Communication Data Analyses Data Set Diagnostic Dimensions Endocrine Ensure Epigenetic Process Estrogen receptor positive Experimental Designs Gene Expression Gene Expression Regulation Genes Genome Genome Components Genomic approach Genomics Goals Hormone Responsive Investigation Leadership Link Malignant Neoplasms Mediating Mitotic Modification Molecular Normal Cell Nuclear Nuclear Structure Oncologist Organoids Pathologist Patients Phenotype Physicians Physiological Process Proteins Protocols documentation Reader Regulation Regulator Genes Reproducibility Research Research Personnel Resistance Resolution Resource Sharing Resources Role Scientist Selective Estrogen Receptor Modulators Seminal Specimen Standardization Therapeutic Time Tissues Transcriptional Regulation Tumor-Derived Untranslated RNA advanced breast cancer aggressive breast cancer bone cancer cell cancer diagnosis cancer therapy cell growth cell transformation chromatin remodeling clinically relevant design epigenome epitranscriptomics experience genetic regulatory protein genome editing genome-wide hormonal signals hormone therapy in vivo in vivo Model innovation insight live cell imaging malignant breast neoplasm mammary epithelium multidisciplinary new technology novel novel strategies operation programs public database response scientific organization synergism therapy resistant transcription factor tumor tumor progression

项目摘要

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.

总体计划摘要计划主管Gary Stein和Janet Stein 我们的计划项目是一个主题，实验和操作整合的多学科团队解决基因组组织的关键组成部分的方法控制乳腺癌基因表达。我们计划的主题重点和工作假设是基因表达的基因组组织和表观遗传控制协同促进生理调节，包括正常和癌细胞生长的激素反应性，增殖和细胞身份。我们高度协作的研究团队建立了范式转移见解进入核组织的参数，包括：1。通过表型转录书签有丝分裂基因书签控制基因表达作为细胞分裂的忠诚度的因素； 2。核保真度之间的关系组织，转录因子定位和乳腺癌转移到骨头； 3。动态修改乳腺癌细胞中高阶和染色体内相互作用； 4。坐标细胞控制组织特异性转录因子的生长和表型； 5。内分泌疗法的表面参考分析抗选择性雌激素受体调节剂的抗性和晚期乳腺癌细胞；和6。侵袭性乳腺癌表型的非编码RNA介导的调节。该应用程序捕捉了我们研究团队和杠杆的科学进步，协同和势头强大的新技术，用于编辑基因组，可视化超级分辨率和实时的细胞，以及解码高阶基因组组织。我们将使用正常的乳腺上皮，亚型特异性和内分泌乳腺癌细胞模型以发现发现，然后验证关键发现并检查潜力使用动物模型，公共数据库以及患者肿瘤标本和器官的临床相关性。重点将是探索整合表观遗传控制多个维度的分子机制与乳腺癌中修改的基因组组织。这三个项目中的每个项目都集中在一个独特的方面基因表达忠诚度所需的表观遗传控制，并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）；溴结构域读取器在内分泌疗法抗性中的新功能（项目2）；和贡献在侵略性乳腺癌中，新型的长期非编码RNA MANCR在侵略性乳腺癌中的基因组组织（项目3）。共享的资源核心将支持综合的生物信息学和生物统计学分析；标准化实验设计；细胞，器官和体内模型；和资源身份验证，以确保科学严格和可重复性。行政核心将最大化科学和程序化集成，优先级和监督。该计划的影响将是多个基因组组织的整合以及表观遗传控制，以了解乳腺癌中基因调节的破坏。