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.

Public Health Relevance

This project investigates the function of a recently described pathway involving the LIN28 RNA binding protein and one of its key targets, the let-7 family of microRNAs. LIN28/let-7 has been implicated in several aspects of human physiology and disease, including the regulation of growth, puberty, metabolism, cancer, and diabetes. Moreover, LIN28 is one of the factors that facilitates the resetting of specialized adult cells back to a state resembling embryonic stem cells, a process termed reprogramming. This application will investigate the mechanism by which LIN28/let-7 influences cell proliferation and metabolism, and will use reprogramming as an accessible in vitro model system to dissect the structure-function relationships of LIN28B and its targets. Insights into how LIN28 is regulated and the impact on its many targets may point towards improved methods to generate stem cells and novel therapeutic interventions in conditions like cancer and diabetes

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Haynes, Susan R
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Children's Hospital Boston
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Tsanov, Kaloyan M; Pearson, Daniel S; Wu, Zhaoting et al. (2017) LIN28 phosphorylation by MAPK/ERK couples signalling to the post-transcriptional control of pluripotency. Nat Cell Biol 19:60-67
Chandrasekaran, Sriram; Zhang, Jin; Sun, Zhen et al. (2017) Comprehensive Mapping of Pluripotent Stem Cell Metabolism Using Dynamic Genome-Scale Network Modeling. Cell Rep 21:2965-2977
Rowe, R Grant; Mandelbaum, Joseph; Zon, Leonard I et al. (2016) Engineering Hematopoietic Stem Cells: Lessons from Development. Cell Stem Cell 18:707-20
Zhang, Jin; Ratanasirintrawoot, Sutheera; Chandrasekaran, Sriram et al. (2016) LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency. Cell Stem Cell 19:66-80
Rowe, R Grant; Wang, Leo D; Coma, Silvia et al. (2016) Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis. J Exp Med 213:1497-512
Corre, Christina; Shinoda, Gen; Zhu, Hao et al. (2016) Sex-specific regulation of weight and puberty by the Lin28/let-7 axis. J Endocrinol 228:179-91
Powers, John T; Tsanov, Kaloyan M; Pearson, Daniel S et al. (2016) Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma. Nature 535:246-51
Tu, Ho-Chou; Schwitalla, Sarah; Qian, Zhirong et al. (2015) LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans. Genes Dev 29:1074-86
Cacchiarelli, Davide; Trapnell, Cole; Ziller, Michael J et al. (2015) Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency. Cell 162:412-424
Wang, L D; Rao, T N; Rowe, R G et al. (2015) The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy. Leukemia 29:1320-30

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