LIN28/let-7 MECHANISMS IN REPROGRAMMING AND METABOLISM

LIN28/let-7 重编程和代谢机制

基本信息

批准号：
8655238
负责人：
George Q Daley
金额：
$ 46.02万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8655238
关键词：
Adult Amino Acids Back Bilateral Biochemical Biogenesis Biological Assay Biological Models Biology Caenorhabditis elegans Catabolism Cataloging Catalogs Cell Line Cell Proliferation Cells Characteristics Data Development Diabetes Mellitus Disease Embryo Enzymes Family Fibroblasts Genes Genetic Screening Genetic Transcription Genomics Germ Cells Glycolysis Growth Histones Homologous Gene Human In Vitro Inflammation Knock-out Light Link Malignant Neoplasms Mammals Mass Spectrum Analysis Measures Metabolic Metabolism Methionine Methods Methylation MicroRNAs Mus Mutation Oncogenic Organism Pathway interactions Pattern Phenotype Physiology Post-Translational Protein Processing Process Proteins Proteome Puberty RNA RNA Binding RNA-Binding Proteins Regulation Reporting Role Sexual Maturation Somatic Cell Stem cells Structure Structure-Activity Relationship System Testing Threonine Time Tissues Transcriptional Regulation Translations Warburg Effect Work cancer genetics diabetes mellitus genetics embryonic stem cell gain of function genome wide association study improved in vitro Model insight knock-down metabolomics mutant novel therapeutic intervention overexpression paralogous gene pluripotency protein protein interaction protein structure small hairpin RNA transcriptome sequencing tumor metabolism

项目摘要

Genetic screens for heterochronic mutants in C. elegans, first reported twenty-eight years ago, defined an evolutionarily conserved pathway controlling growth and developmental timing in all bilateral organisms, and from which emerged the discovery of microRNAs. We discovered a fundamental biochemical mechanism that relates two mammalian homologues of heterochronic worm genes: the RNA binding protein LIN28 inhibits the biogenesis of let-7 microRNAs (miRNAs). We and others have implicated LIN28/let-7 in a sweeping range of biology including mammalian growth and developmental timing of sexual maturation, somatic cell reprogramming and pluripotency, germ cell development, cancer, inflammation, glycolytic metabolism, and diabetes. Our recent data connects the LIN28/let-7 axis to the shift towards glycolytic metabolism that accompanies reprogramming of somatic cells to pluripotency. We have also linked LIN28/let-7 to the distinctive amino acid metabolism of embryonic and pluripotent cells, in which flux through Threonine/ Methionine influences levels of s-adenosyl methionine, histone H3K4 methylation, and pluripotency. The ancestral C. elegans LIN28 gene exists in mammals as two highly related paralogs, A and B, which show different temporal and spatial patterns of tissue expression, different protein structures and modifications, and different RNA targets. This proposal will analyze transcriptional regulation, structure/function relationships, post- translational modifications, and effects on the proteome of the two paralogs in the context of somatic cell reprogramming and metabolism, testing the hypothesis that LIN28 confers a glycolytic metabolic state characteristic of embryonic and pluripotent cells. Illuminating the LIN28/let-7 pathway will provide fundamental insights into reprogramming while also shedding light on disease processes like cancer and diabetes. Understanding its mechanisms is destined to have major significance for biomedicine.

秀丽隐杆线虫异时突变体的遗传筛选，于二十八年前首次报道，定义了一条进化上保守的途径，控制所有生物的生长和发育时间双侧生物体，并从中发现了 microRNA。我们发现了一个与异时性的两个哺乳动物同源物相关的基本生化机制蠕虫基因：RNA 结合蛋白 LIN28 抑制 let-7 microRNA 的生物发生（miRNA）。我们和其他人已经将 LIN28/let-7 与广泛的生物学联系起来，包括哺乳动物的生长和性成熟的发育时间，体细胞重编程和多能性、生殖细胞发育、癌症、炎症、糖酵解代谢，以及糖尿病。我们最近的数据将 LIN28/let-7 轴与向糖酵解的转变联系起来伴随体细胞重编程至多能性的新陈代谢。我们还有将 LIN28/let-7 与胚胎和多能细胞的独特氨基酸代谢联系起来，通过苏氨酸/蛋氨酸的通量影响 s-腺苷蛋氨酸、组蛋白的水平 H3K4 甲基化和多能性。线虫祖先 LIN28 基因存在于哺乳动物中作为两个高度相关的旁系同源物 A 和 B，它们表现出不同的时间和空间模式组织表达、不同的蛋白质结构和修饰以及不同的 RNA 靶标。这该提案将分析转录调控、结构/功能关系、后翻译修饰以及对两个旁系同源物蛋白质组的影响体细胞重编程和代谢，检验 LIN28 赋予体细胞重编程和代谢的假设胚胎和多能细胞的糖酵解代谢状态特征。照亮 LIN28/let-7 通路将为重新编程提供基本见解，同时也可脱落阐明癌症和糖尿病等疾病过程。了解其机制是注定的对生物医学具有重大意义。