Microbial and inflammatory regulation of intestinal epithelial gene transcription

肠上皮基因转录的微生物和炎症调节

• 批准号: 10216243
• 负责人: John F Rawls
• 金额: $ 36.54万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216243
• 关键词: Anti-Inflammatory Agents; Cell Communication; Cell physiology; Cellular biology; ChIP-seq; Characteristics; Complex; Coupled; DNA; DNA Binding; Data; Data Set; Diagnosis; ELF3 gene; ETS Family Protein; Enhancers; Epithelial; Epithelial Cells; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Gnotobiotic; Goals; HNF4A gene; Health; Histone Acetylation; Histone Deacetylase; Homeostasis; Human; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Knock-out; Knowledge; Lead; Mediating; Mediator of activation protein; Microbe; Mission; Modeling; Mucous Membrane; Mus; Mutation Analysis; Nuclear Receptors; Orthologous Gene; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Prevention; Public Health; Regulation; Regulatory Pathway; Research; Role; Sampling; Signal Transduction; Stimulus; Symbiosis; System; Testing; Therapeutic; Transcriptional Regulation; United States National Institutes of Health; Zebrafish; base; burden of illness; clinical phenotype; cofactor; disease phenotype; genetic corepressor; genome wide association study; gut microbes; gut microbiota; histone acetyltransferase; host-microbe interactions; human disease; improved; in vivo; inflammatory disease of the intestine; insight; intestinal epithelium; intestinal homeostasis; microbial; microbiota; microorganism; mutant; novel; novel diagnostics; novel strategies; prognostic; programs; response; transcription factor; transcription factor USF; translational study

ABSTRACT There exist fundamental gaps in our understanding of the transcriptional regulatory pathways through which microbiota and inflammation alter gene expression in the intestinal epithelium, and how those pathways promote and might predict intestinal homeostasis. Our long-term goal is to understand the evolutionarily-conserved mechanisms underlying host-microbe interactions in the intestine and how they contribute to human diseases. The overall objectives of this project are to identify conserved transcriptional regulatory pathways mediating intestinal epithelial cell (IEC) responses to microbiota and inflammation, and determine if their activity can be used as phenotypic indicators in human inflammatory bowel disease (IBD). Our preliminary studies in human, mouse, and zebrafish IECs have uncovered striking conservation of transcriptional signatures and regulatory mechanisms, predicting central conserved roles for transcription factors (TF) implicated in human IBD including HNF4A and ELF3. We recently made the key discovery that HNF4A is a novel mediator of IEC transcriptional responses to microbiota in zebrafish and mice. Mechanistic studies in zebrafish and mice revealed that HNF4A is a positive regulator of microbially-suppressed genes, and that microbiota broadly suppress HNF4A activity in IECs. Further, our results show that intestinal suppression of HNF4A target genes is a prevalent feature of human, mouse, and zebrafish models of IBD, and indicate that HNF4A constrains inflammatory responses to microbiota and suppresses a conserved IBD-like gene expression signature. Finally, we identified DNA enhancer elements in mouse IECs that are regulated by microbiota colonization, and leverage those results to implicate ELF3 as a potential integrator of inflammatory and microbial signals in IECs. We will test the central hypothesis that microbiota promote intestinal inflammation by coordinately suppressing anti-inflammatory HNF4A activity and activating ELF3 and other pro-inflammatory transcriptional pathways. In Specific Aim 1, we will identify host signaling mechanisms mediating microbial suppression of HNF4A activity in IECs. In Specific Aim 2, we will define the roles of ELF3 and broader transcriptional pathways in IEC responses to microbiota and inflammation, and test if IBD phenotypes are associated with distinct signatures of ELF3 and HNF4A activity. The expected outcomes will vertically advance the field in several ways. First, they will generate a foundational mechanistic understanding of how gut microbes regulate the activity of HNF4A and ELF3, conserved TFs with critical roles in intestinal inflammation. Second, they will provide much-needed insights into the transcriptional regulatory networks utilized by IECs to integrate microbial and inflammatory stimuli, and how those networks are deranged in human IBD. These outcomes are expected to have a significant impact because they will vertically advance our understanding of the IEC transcriptional programs that integrate responses to microbiota and inflammation, which can be expected to lead to new diagnostic, prognostic, and therapeutic approaches for human IBD.

抽象的 我们对转录调控途径的理解存在根本性差距 微生物群和炎症改变肠上皮的基因表达，以及这些途径如何促进 并可能预测肠道稳态。我们的长期目标是了解进化保守的 肠道中宿主与微生物相互作用的机制以及它们如何导致人类疾病。 该项目的总体目标是确定介导的保守转录调控途径 肠上皮细胞 (IEC) 对微生物群和炎症的反应，并确定它们的活性是否可以 用作人类炎症性肠病（IBD）的表型指标。我们对人类的初步研究， 小鼠和斑马鱼 IEC 发现了转录特征和调控的显着保守性 机制，预测与人类 IBD 相关的转录因子 (TF) 的中心保守作用，包括 HNF4A 和 ELF3。我们最近做出了重要发现，HNF4A 是 IEC 转录的新型介质 斑马鱼和小鼠对微生物群的反应。斑马鱼和小鼠的机制研究表明，HNF4A 是微生物抑制基因的正调节因子，微生物群广泛抑制 HNF4A 活性 IEC。此外，我们的结果表明 HNF4A 靶基因的肠道抑制是 人类、小鼠和斑马鱼 IBD 模型，并表明 HNF4A 抑制炎症反应 微生物群并抑制保守的 IBD 样基因表达特征。最后，我们确定了 DNA 增强子 小鼠 IEC 中受微生物群定植调节的元素，并利用这些结果来暗示 ELF3 作为 IEC 中炎症和微生物信号的潜在整合者。我们将检验中心假设 微生物群通过协调抑制抗炎 HNF4A 活性来促进肠道炎症 并激活 ELF3 和其他促炎转录途径。在具体目标 1 中，我们将确定主机 IEC 中介导微生物抑制 HNF4A 活性的信号机制。在具体目标 2 中，我们将 定义 ELF3 和更广泛的转录途径在 IEC 对微生物群和炎症反应中的作用， 并测试 IBD 表型是否与 ELF3 和 HNF4A 活性的不同特征相关。预期的 结果将以多种方式垂直推进该领域。首先，他们将产生一个基本机制 了解肠道微生物如何调节 HNF4A 和 ELF3（具有关键作用的保守转录因子）的活性 在肠道炎症中。其次，他们将为转录调控提供急需的见解 IEC 用来整合微生物和炎症刺激的网络，以及这些网络是如何紊乱的 在人类 IBD 中。这些成果预计将产生重大影响，因为它们将垂直推进 我们对整合微生物群和炎症反应的 IEC 转录程序的理解， 预计这将为人类 IBD 带来新的诊断、预后和治疗方法。