title: A Single Let-7 MicroRNA Bypasses LIN28-Mediated Repression.
abstract: Let-7 microRNAs (miRNAs) are critical regulators of animal development, stem cell differentiation, glucose metabolism, and tumorigenesis. Mammalian genomes contain 12 let-7 isoforms that suppress expression of a common set of target mRNAs. LIN28 proteins selectively block let-7 biogenesis in undifferentiated cells and in cancer. The current model for coordinate let-7 repression involves the LIN28 cold-shock domain (CSD) binding the terminal loop and the two CCHC-type zinc fingers recognizing a GGAG sequence motif in precursor let-7 (pre-let-7) RNAs. Here, we perform a systematic analysis of all let-7 miRNAs and find that a single let-7 family member, human let-7a-3 (and its murine ortholog let-7c-2), escapes LIN28-mediated regulation. Mechanistically, we find that the pre-let-7c-2 loop precludes LIN28A binding and regulation. These findings refine the current model of let-7 regulation by LIN28 proteins and have important implications for understanding the LIN28/let-7 axis in development and disease.
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Robinson
authors.initials: R
authors.lastname: Triboulet
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Pirouz
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rgregory@enders.tch.harvard.edu.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
mesh_terms: D000818:Animals; D001483:Base Sequence; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C000715187:Lin28A protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; C542687:mirnlet7 microRNA, mouse