Defining cis-regulatory networks controlling a core stress response

摘要 我们的研究计划的目标是剖析建立和活动的机制。 顺式调控元件及其对转录基因网络的控制。我们专注于蜂窝网络 对DNA损伤的反应，一个保守的途径，需要保持基因组的保真度和整体 生物动态平衡。在这一资助期间，我们将重点关注转录因子p53的活性， 它在DNA损伤基因调控网络中扮演着中心枢纽的角色。P53活性的错误调节是 直接与许多人类疾病有关，但我们缺乏对p53如何控制细胞命运的关键洞察力 暴露于DNA损伤后的决定。我们已经产生了一组新的假设，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来维持基因组的保真度。我们的团队利用先进的遗传、表观遗传和基因组工程 结合经典遗传和生化模型解析调控的机制贡献 元件、染色质结构和转录因子对DNA损伤反应的转录和活性 最终，细胞命运的决定。定位控制DNA损伤的功能网络和机制 应对措施将极大地拓宽我们对人类发展、老龄化的理解，并朝着 治疗性细胞重编程范例和基因组编辑的分子控制。

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.