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Early Environment, Developmental Epigenetics, and Adult Colonic Diseases

早期环境、发育表观遗传学和成人结肠疾病

基本信息

批准号：
10579855
负责人：
Lanlan Shen
金额：
$ 30.46万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-07 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579855
关键词：
Aberrant DNA Methylation Adult Age Behavior Binding Binding Sites Biological Assay Birth CCCTC-binding factor Carbon ChIP-seq Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Colitis Colonic Diseases Colorectal Cancer CpG Islands DNA DNA Methylation Data Defect Development Disease Disease susceptibility Enhancers Environment Epigenetic Process Epithelial Cells Folic Acid Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomic Segment Germ-Free Gnotobiotic Goals Health Heritability Homocysteine Human Human Microbiome Individual Inflammation Inflammatory Bowel Diseases Inherited Intestinal Diseases Intestines LGR5 gene Lead Life Link Luciferases Mammals Maps Mediating Methylation Mitotic Modeling Molecular Mus Neonatal Nutrient Organoids Pathogenesis Pathway interactions Personal Satisfaction Play Predisposition Process Reaction Regulation Reporter Research Role S-Adenosylhomocysteine S-Adenosylmethionine Structure of intestinal gland System Techniques Technology Testing Tissues Transcriptional Activation Vitamin B 12 Weaning Work cell type critical period demethylation design dietary early childhood effective intervention epigenetic memory epigenetic regulation epigenome epigenome editing gene environment interaction gene function genome-wide germ free condition glycosylation gut microbes gut microbiome gut microbiota host microbiome host-microbe interactions improved infancy insight interest intestinal epithelium knock-down methylome microbial microbial colonization microbiome microbiota mouse model postnatal prevent promoter stem cell biomarkers stem cell function stem cell self renewal stem cells suckling therapy development tool transcription factor transcriptome transmission process tumorigenesis

项目摘要

PROJECT SUMMARY Gut microbial colonization in early postnatal life plays a crucial role in mammalian intestinal development. It has long been postulated that DNA methylation, as an epigenetic mechanism to control gene expression, is involved in intestinal host-microbial interactions. The high turnover of intestinal epithelial cells throughout life makes intestinal stem cells (ISCs) critically important for gut function. Remarkably, however, how the mechanisms underlying the effects of the gut microbiota on DNA methylation to regulate the emergence and behavior of adult ISCs remain poorly understood. Improving our understanding of this process is fundamental for human health because intestinal epithelium is one of the major tissue targets of inflammation and tumorigenesis, and aberrant DNA methylation as well as alterations of the gut microbiota are increasingly recognized to be critical for disease pathogenesis. The proposed research extends our previous work that identified a subset of 3’ CpG islands (3’ CGIs) that are methylated in ISCs during the suckling period in mice. We demonstrated that 3’ CGI methylation transmits an epigenetic memory associated with stable gene activation in adult ISCs. In addition, we discovered that 3’ CGI methylation is uniquely vulnerable to gut microbiota perturbations. Therefore, the goal of the proposed research is to further elucidate the mechanisms of epigenetic regulation in developing ISCs. Our hypothesis is that postnatally established epigenetic memory by 3’ CGI methylation provides a developmental pathway for regulating intestinal host-microbiome interactions with lifelong functional consequences. We propose the following three specific aims: (i) Define the mechanism by which 3’ CGI methylation regulates intestinal gene activation, (ii) Define the mechanism by which the gut microbiota regulates 3’ CGI methylation, and (iii) Define the long-term function of microbiota-responsive 3’ CGI methylation. We will capitalize on recent technological advancements enabling isolation of Lgr5+ ISCs; apply state-of-the-art techniques to achieve the ultimate genome-wide, unbiased assessment of the microbiome effects on the ISC epigenome; and use cutting-edge organoid and CRISPR epigenome editing tools to dissect the microbiota-mediated epigenetic mechanisms that regulate ISC function. The successful completion of these studies will yield important insights into the functional role of DNA methylation during intestinal development, advancing our understanding of the molecular basis of gene-environment interactions in the intestine. Furthermore, the mechanistic insight gained from these studies offers great promise for development of interventions and treatments of intestinal diseases.

项目概要产后早期肠道微生物定植在哺乳动物肠道发育中起着至关重要的作用。它长期以来，人们一直认为 DNA 甲基化作为控制基因表达的表观遗传机制，参与肠道宿主-微生物相互作用。整个生命过程中肠上皮细胞的高周转率使得肠道干细胞 (ISC) 对肠道功能至关重要。然而值得注意的是，如何肠道微生物群对 DNA 甲基化影响的机制，以调节出现和成人 ISC 的行为仍然知之甚少。提高我们对这一过程的理解至关重要对人类健康有益，因为肠上皮是炎症和炎症的主要组织靶标之一肿瘤发生、异常 DNA 甲基化以及肠道微生物群的改变越来越多被认为对疾病发病机制至关重要。拟议的研究扩展了我们之前的工作鉴定了 3' CpG 岛 (3' CGI) 的一个子集，这些岛在小鼠哺乳期的 ISC 中被甲基化。我们证明 3'CGI 甲基化传递与稳定基因相关的表观遗传记忆成人 ISC 的激活。此外，我们发现 3'CGI 甲基化特别容易受到肠道的影响微生物群扰动。因此，本研究的目的是进一步阐明其机制发育中 ISC 的表观遗传调控。我们的假设是，出生后建立的表观遗传记忆 3’ CGI 甲基化提供了调节肠道宿主-微生物组相互作用的发育途径具有终生的功能后果。我们提出以下三个具体目标： (i) 明确机制 3' CGI 甲基化通过其调节肠道基因激活，(ii) 定义肠道基因激活的机制微生物群调节 3' CGI 甲基化，以及 (iii) 定义微生物群响应性 3' CGI 的长期功能甲基化。我们将利用最新的技术进步来实现 Lgr5+ ISC 的分离；申请最先进的技术，以实现对微生物组进行最终的全基因组、公正的评估对 ISC 表观基因组的影响；并使用尖端的类器官和 CRISPR 表观基因组编辑工具来解剖微生物介导的表观遗传机制调节 ISC 功能。顺利完成这些研究将对肠道中 DNA 甲基化的功能作用产生重要的见解。的发展，增进我们对基因与环境相互作用的分子基础的理解肠。此外，从这些研究中获得的机制见解为发展提供了巨大的希望肠道疾病的干预和治疗。