title: mRNA destabilization is the dominant effect of mammalian microRNAs by the time substantial repression ensues.
abstract: MicroRNAs (miRNAs) regulate target mRNAs through a combination of translational repression and mRNA destabilization, with mRNA destabilization dominating at steady state in the few contexts examined globally. Here, we extend the global steady-state measurements to additional mammalian contexts and find that regardless of the miRNA, cell type, growth condition, or translational state, mRNA destabilization explains most (66%->90%) miRNA-mediated repression. We also determine the relative dynamics of translational repression and mRNA destabilization for endogenous mRNAs as a miRNA is induced. Although translational repression occurs rapidly, its effect is relatively weak, such that by the time consequential repression ensues, the effect of mRNA destabilization dominates. These results imply that consequential miRNA-mediated repression is largely irreversible and provide other insights into the nature of miRNA-mediated regulation. They also simplify future studies, dramatically extending the known contexts and time points for which monitoring mRNA changes captures most of the direct miRNA effects.
authors.affiliation: Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Eichhorn
authors.affiliation: Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute of Molecular and Cell Biology, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University-Imperial College, Singapore 639798, Singapore.
authors.forename: Huili
authors.initials: H
authors.lastname: Guo
authors.affiliation: Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sean E
authors.initials: SE
authors.lastname: McGeary
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Ricard A
authors.initials: RA
authors.lastname: Rodriguez-Mias
authors.affiliation: Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Agricultural Biotechnology, Plant Genomics and Breeding Institute, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Chanseok
authors.initials: C
authors.lastname: Shin
authors.affiliation: Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Center for RNA Research, Institute for Basic Science, Seoul 151-747, Republic of Korea; School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea; Bioinformatics Institute, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Daehyun
authors.initials: D
authors.lastname: Baek
authors.affiliation: Department of Pathology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Shu-Hao
authors.initials: SH
authors.lastname: Hsu
authors.affiliation: Department of Pathology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Villén
authors.affiliation: Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: dbartel@wi.mit.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Bartel
mesh_terms: D005786:Gene Expression Regulation; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008957:Models, Genetic; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger