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Transcriptional events controlling enteroendocrine cell differentiation

控制肠内分泌细胞分化的转录事件

基本信息

批准号：
9160624
负责人：
ANDREW B. LEITER
金额：
$ 37.69万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9160624
关键词：
Accounting Acetylation Automobile Driving BHLH Protein Binding Binding Sites Biogenic Amines Blood Cataloging Catalogs Cell Differentiation process Cell Line Cell Lineage Cells Chromatin Chromatin Structure Complex DNA Data Desire for food Diabetes Mellitus Disease Eating Endocrine Enhancers Ensure Enteroendocrine Cell Environment Epithelial Cells Event Figs - dietary Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Transcription Genome Genomics Goals High-Throughput Nucleotide Sequencing Homeostasis Hormones Individual Intestines Islets of Langerhans Knowledge Label Link Maps Mus National Human Genome Research Institute Non-Insulin-Dependent Diabetes Mellitus Obesity Organ PCAF gene Production Proteins Role STC1 gene Site Sp1 Transcription Factor Staging Stem cells Tissue-Specific Gene Expression Tissues Transcript Transcription Coactivator Transgenic Mice Variant Work cell type genome wide association study in vivo insulin secretion intestinal epithelium intestinal homeostasis knock-down member novel novel therapeutics peptide hormone programs protein expression self-renewal transcription factor transcriptome sequencing

项目摘要

Project Description Enteroendocrine cells (EECs) are one of five epithelial cell lineages in the intestine that arise from intestinal stem cells. EECs are notable for their secretion of peptide hormones and biogenic amines. Secreted products regulate food intake, energy homeostasis, insulin secretion and the function of most digestive organs. Relatively little is known about the transcriptional programs that drive enteroendocrine cell differentiation. Until recently, it has difficult to isolate enough EECs for gene expression analysis since EECs represent less than 2% of the intestinal epithelium. The ability to collect fluorescently labeled EECs from transgenic mice combined with technological improvements in high throughput sequencing, make it possible to consider gene expression studies in EECs that previously could not be done. Two basic helix loop helix transcription factors are critical for EEC differentiation. Neurogenin3 (Neurog3) is required for the earliest stages of EEC specification but can give rise to nonendocrine cell types. Expression of the bHLH protein NeuroD1 is expressed in all EECs, restricting cells to an endocrine cell fate. As a relatively weak transcriptional activator, it is not known how NeuroD1 drives cells to become EECs. Our understanding is further limited by the paucity of identified NeuroD1 targets in enteroendocrine cells. An increasing body of information has revealed that tissue specific expression depends on both the local chromatin environment and enhancer occupancy by multiple tissue specific transcription factors. The overall goals of this proposal are to identify NeuroD1 transcriptional targets, to identify other proteins that occupy sites close to NeuroD1, and determine how NeuroD1 activity is influenced by the local chromatin environment. In addition, the contribution of ubiquitously expressed transcription factors bound to nearby sites, to NeuroD1 transcriptional activity will be examined. The goal of Aim 1 is to identify genes that are activated by NeuroD1 in EECs and to identify other transcription factors that bind to DNA in close proximity with NeuroD1 to enhance target gene expression. Studies in Aim 2 will examine the broad role of RREB1 and LSD1, two members of the CtBP co-repressor complex that associate with NeuroD1 to potentiate transcription. The goal of Aim 3 is to determine the importance open chromatin subtypes and enhancer occupancy by multiple transcription factors in NeuroD1 driven tissue specific gene expression. The final goal of Aim3 will be to determine if any identified NeuroD1 enhancer clusters are linked to disease associated variants (SNPs) in the GWAS catalogue. Completion of the proposed studies will expand our knowledge about enteroendocrine cell differentiation and their potential impact on common diseases like diabetes and obesity.

项目描述