Defining cis-regulatory networks controlling a core stress response

摘要 我们的研究计划的目标是剖析的建立和活动的机制， 顺式调控元件及其对转录基因网络的控制。我们专注于细胞 对DNA损伤的反应，这是一种保存基因组保真度和整体 生物体内平衡在此资助期间，我们将重点关注转录因子p53的活性， 其在DNA损伤基因调控网络中充当中心枢纽。p53活性的失调是 p53与许多人类疾病直接相关，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基因组结构与 p53以维持基因组保真度。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物化学模型来解析调控的机制贡献， 元件、染色质结构和转录因子活性对DNA损伤反应转录的影响， 最终决定细胞命运绘制控制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，并建立精确的 分子控制治疗细胞重编程范例和基因组编辑。

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.