Defining cis-regulatory networks controlling a core stress response

定义控制核心应激反应的顺式调节网络

• 批准号: 10029037
• 负责人: Morgan Andrew Sammons
• 金额: $ 26.2万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029037
• 关键词: 3-Dimensional; Aging; Cell Fate Control; Cell Proliferation; Cells; Chromatin Structure; Complex; DNA Damage; Development; Disease; Engineering; Epigenetic Process; Event; Exposure to; Funding; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Genomics; Goals; Homeostasis; Human; Human Development; Infertility; Investigation; Malignant Neoplasms; Molecular; Pathway interactions; Premature aging syndrome; Regulator Genes; Regulatory Element; Research; Structure; TP53 gene; Therapeutic; Time; Transcriptional Regulation; Work; biochemical model; biological adaptation to stress; combinatorial; fitness; genome editing; human disease; insight; novel; preservation; programs; response; stem cells; transcription factor

ABSTRACT The goal of our research program is to dissect the mechanisms underlying the establishment and activity of cis-regulatory elements and their control of transcriptional gene networks. We are focused on the cellular response to DNA damage, a well-conserved pathway required for preservation of genome fidelity and overall organismal homeostasis. During this funding period, we will focus on the activity of the transcription factor p53, which acts a central hub within the DNA damage gene regulatory network. Misregulation of p53 activity is directly implicated in numerous human diseases, but we lack key insight into how p53 controls cell fate decisions after exposure to DNA damage. We have generated a set of novel hypotheses regarding how cis- regulatory elements, combinatorial transcription factor activity, and 3D genome structure work in concert with p53 to maintain genome fidelity. Our group utilizes advanced genetic, epigenetic, and genomic engineering combined with classical genetic and biochemical models to parse the mechanistic contributions of regulatory elements, chromatin structure, and transcription factor activity to DNA damage response transcription and ultimately, cell fate determination. Mapping functional networks and mechanisms controlling the DNA damage response will significantly broaden our understanding of human development, aging, and build towards precise molecular control over therapeutic cellular reprogramming paradigms and genome editing.

抽象的 我们研究计划的目标是剖析建立和活动的潜在机制 顺式调控元件及其对转录基因网络的控制。我们专注于蜂窝 对 DNA 损伤的反应，这是保存基因组保真度和整体基因组所需的保守途径 机体稳态。在本次资助期间，我们将重点关注转录因子p53的活性， 它充当 DNA 损伤基因调控网络的中心枢纽。 p53 活性的错误调节是 直接涉及许多人类疾病，但我们缺乏对 p53 如何控制细胞命运的关键见解 暴露于 DNA 损伤后的决定。我们已经提出了一系列关于顺式- 调控元件、组合转录因子活性和 3D 基因组结构协同工作 p53 维持基因组保真度。我们的团队利用先进的遗传、表观遗传和基因组工程 结合经典的遗传和生化模型来解析监管的机制贡献 元素、染色质结构和转录因子活性对 DNA 损伤反应的转录和 最终，细胞的命运决定。绘制控制 DNA 损伤的功能网络和机制 响应将大大拓宽我们对人类发展、老龄化的理解，并朝着精确的目标迈进 对治疗性细胞重编程范例和基因组编辑的分子控制。