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 allbilateral organisms, and from which emerged the discovery of microRNAs. We discovered afundamental biochemical mechanism that relates two mammalian homologues of heterochronicworm 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 includingmammalian growth and developmental timing of sexual maturation, somatic cell reprogrammingand pluripotency, germ cell development, cancer, inflammation, glycolytic metabolism, anddiabetes. Our recent data connects the LIN28/let-7 axis to the shift towards glycolyticmetabolism that accompanies reprogramming of somatic cells to pluripotency. We have alsolinked LIN28/let-7 to the distinctive amino acid metabolism of embryonic and pluripotent cells, inwhich flux through Threonine/ Methionine influences levels of s-adenosyl methionine, histoneH3K4 methylation, and pluripotency. The ancestral C. elegans LIN28 gene exists in mammalsas two highly related paralogs, A and B, which show different temporal and spatial patterns oftissue expression, different protein structures and modifications, and different RNA targets. Thisproposal will analyze transcriptional regulation, structure/function relationships, post-translational modifications, and effects on the proteome of the two paralogs in the context ofsomatic cell reprogramming and metabolism, testing the hypothesis that LIN28 confers aglycolytic metabolic state characteristic of embryonic and pluripotent cells. Illuminating theLIN28/let-7 pathway will provide fundamental insights into reprogramming while also sheddinglight on disease processes like cancer and diabetes. Understanding its mechanisms is destinedto have major significance for biomedicine.