Dissecting mechanisms of gene control in the vertebrate acute phase response

解析脊椎动物急性期反应中基因控制的机制

• 批准号: RGPIN-2019-07041
• 负责人: Wilson, Michael
• 金额: $ 2.19万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716217
• 关键词: Dissecting; mechanisms; gene; control; vertebrate

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.

我的研究项目探索基因是如何被调控的，它植根于适用于所有生物体的基本生物学问题。特别是，我的实验室专注于脊椎动物基因组中由转录因子结合的非编码区。转录因子是与DNA结合并调节基因表达的蛋白质。通过实验确定不同脊椎动物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特征进化的相对贡献是什么？2)组织特异性基因调控在进化过程中是如何维持的？ 这项研究的具体目标是研究健康肝脏在面对压力、有害刺激和损伤时做出快速反应的基因调控机制。这种反应被称为急性时相反应(APR)。APR的许多方面在脊椎动物中都是保守的，这种保守也延伸到无脊椎动物。除了保守的APR基因外，还观察到了许多物种特异性的APR基因。令人惊讶的是，关于基因调控的变化是如何在进化过程中塑造APR的，人们知之甚少。 通过研究APR的进化，我们将确定哺乳动物APR基因的核心集合，并对控制它们的机制有具体的了解。我们将在从四种脊椎动物分离的肝细胞(肝细胞)中鉴定靶APR基因。我们将生成这些物种APR的原始转录因子结合图和染色质可及性图。我们将测试保守的调节区对APR的重要性程度，并识别在特定物种中修改APR的基因组创新。总体而言，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的保守和物种特有的成分将对兽医和农业具有潜在的价值。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方面的高素质人才。