LIN28/let-7 MECHANISMS IN REPROGRAMMING AND METABOLISM

异时突变体的遗传筛选。28年前首次报道的秀丽线虫， 定义了一个进化上保守的途径，控制所有动物的生长和发育时间。 双边生物，并从中出现了microRNA的发现。我们发现了一 一种基本的生化机制，涉及两种哺乳动物同源的异时 蠕虫基因：RNA结合蛋白LIN 28抑制let-7 microRNA的生物合成 （miRNAs）。我们和其他人已经将LIN 28/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， 糖尿病我们最近的数据将LIN 28/let-7轴与糖酵解转变联系起来 这是伴随体细胞重编程为多能性的代谢。我们还 将LIN 28/let-7与胚胎和多能细胞的独特氨基酸代谢联系起来， 其通过苏氨酸/蛋氨酸的通量影响s-腺苷甲硫氨酸、组蛋白 H3 K4甲基化和多能性。祖先C。哺乳动物中存在线虫LIN 28基因 作为两个高度相关的旁系同源物，A和B，它们显示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 建议将分析转录调控，结构/功能关系，后 翻译修饰，以及对两种旁系同源物蛋白质组的影响， 体细胞重编程和代谢，测试LIN 28赋予一个 胚胎和多能细胞的糖酵解代谢状态。照亮 LIN 28/let-7通路将为重编程提供基本见解，同时还将脱落 对癌症和糖尿病等疾病过程的了解。了解其机制， 对生物医学有重大意义。

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.