title: A novel mechanism of LIN-28 regulation of let-7 microRNA expression revealed by in vivo HITS-CLIP in C. elegans.
abstract: The evolutionarily conserved gene lin-28 encodes an RNA-binding protein and is an important regulator of the proper temporal succession of several developmental events in both invertebrates and vertebrates. At the cellular level, LIN-28 promotes stemness and proliferation, and inhibits differentiation, a feature best illustrated by its ability to induce pluripotency when ectopically expressed in human fibroblasts in combination with NANOG, OCT4, and SOX2. Mammalian LIN28 functions in part by regulating processing of the let-7 microRNA through a GGAG binding site in the pre-let-7's distal loop region. However, many human and animal let-7 precursors lack the GGAG binding motif. In order to dissect the molecular mechanisms underlying its biological functions in a living animal, we identified a map of LIN-28 interactions with the transcriptome by in vivo HITS-CLIP in Caenorhabditis elegans. LIN-28 binds a large pool of messenger RNAs, and a substantial fraction of the bona fide LIN-28 targets are involved in aspects of animal development. Furthermore, our data show that LIN-28 regulates the expression of the let-7 microRNA by binding its primary transcript in a previously unknown region, revealing a novel regulatory mechanism.
authors: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06405, USA Centre for Integrative Biology (CIBIO), University of Trento, 38123 Povo (TN), Italy.
authors: Giovanni
authors: G
authors: Stefani
authors: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06405, USA Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06511, USA.
authors: Xiaowei
authors: X
authors: Chen
authors: Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06511, USA Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut 06511, USA Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors: Hongyu
authors: H
authors: Zhao
authors: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06405, USA.
authors: Frank J
authors: FJ
authors: Slack
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism / Q000502:physiology*; D002874:Chromosome Mapping / Q000379:methods*; D017124:Conserved Sequence; D018507:Gene Expression Regulation, Developmental; D015723:Gene Library; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010802:Phylogeny; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; C452195:LIN-28 protein, C elegans; D035683:MicroRNAs; D012097:Repressor Proteins; C474488:let-7 microRNA, C elegans
keywords: HITS-CLIP; LIN-28; RNA-binding; let-7; miRNA