LIN28/let-7 MECHANISMS IN REPROGRAMMING AND METABOLISM

Boston Children'S Hospital, Boston MA

Investigators

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Abstract

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.