Dissecting mechanisms of gene control in the vertebrate acute phase response

我的研究项目探索基因如何受到调节，以适用于所有生物体的基本生物学问题为基础。我的实验室特别关注脊椎动物基因组中与转录因子结合的非编码区域。转录因子是与 DNA 结合并调节基因表达的蛋白质。通过实验确定来自不同脊椎动物物种的健康组织或细胞中的转录因子-DNA 相互作用、RNA 表达、染色质可及性和长程染色质相互作用，我们正在解决进化生物学中的基本问题，包括：1）DNA 中蛋白质编码和非蛋白质编码变化对新性状进化的相对贡献是什么？ 2）在进化过程中组织特异性基因调控是如何维持的？ 这项研究的具体目标是研究健康肝脏在面临压力、有害刺激和损伤时快速反应的基因调控机制。这种反应被称为急性期反应（APR）。 APR 的许多方面在脊椎动物中都是保守的，这种保守性也延伸到无脊椎动物中。除了保守的 APR 基因外，还观察到许多物种特异性的 APR 基因。令人惊讶的是，人们对进化过程中基因调控的变化如何影响 APR 知之甚少。 通过研究 APR 的进化，我们将确定一组核心的哺乳动物 APR 基因，并获得对控制它们的机制的具体了解。我们将鉴定从四种脊椎动物中分离的肝细胞（肝细胞）中的目标 APR 基因。我们将生成这些物种中 APR 的原始转录因子结合和染色质可及性图。我们将测试保守调控区域对 APR 的重要性，并确定在特定物种中修改 APR 的基因组创新。总的来说，这项工作将使我们能够在脊椎动物基因控制的进化方面取得新的发现。了解 APR 的保守成分和物种特异性成分对于兽医学和农业具有潜在价值。我们的多学科培训研究计划将培养生物信息学和基因组学领域的高素质人才。

My research program, which explores how genes are regulated, is grounded in basic biological questions that apply to all organisms. In particular, my lab is focused on the non-coding regions of the vertebrate genome that are bound by transcription factors. Transcription factors are proteins that bind to DNA and regulate the expression of genes. By experimentally determining transcription factor-DNA interactions, RNA expression, chromatin accessibility, and long-range chromatin interaction in healthy tissues or cells from different vertebrate species, we are addressing fundamental questions in evolutionary biology including: 1) What are the relative contributions of protein-coding and non-protein coding changes in DNA to the evolution of new traits? and 2) How is tissue-specific gene regulation maintained during evolution? The specific objectives of this research is to study gene regulatory mechanisms underlying a rapid response made by healthy livers when faced with stress and noxious stimuli and injury. This response has been called the acute-phase response (APR). Many aspects of the APR have been conserved in vertebrates and this conservation also extends to invertebrates. In addition to conserved APR genes, many species-specific APR genes have been observed. There is surprisingly little known about how changes in gene regulation have shaped the APR during evolution. By studying the evolution of the APR we will identify a core set of mammalian APR genes and gain specific insight into the mechanisms that control them. We will identify target APR genes in liver cells (hepatocytes) isolated from four vertebrate species. We will generate original transcription factor binding and chromatin accessibility maps of the APR in these species. We will test the extent to which conserved regulatory regions are the important for the APR and identify genome innovations which have modified the APR in a specific species. Overall, this work will allow us to make new discoveries regarding the evolution of vertebrate gene control. Knowing the conserved and species-specific components of the APR will be potentially valuable for veterinary medicine and agriculture. Our multidisciplinary training research program will result in training highly qualified personnel in bioinformatics and genomics.