title: Gene expression. MicroRNA control of protein expression noise.
abstract: MicroRNAs (miRNAs) repress the expression of many genes in metazoans by accelerating messenger RNA degradation and inhibiting translation, thereby reducing the level of protein. However, miRNAs only slightly reduce the mean expression of most targeted proteins, leading to speculation about their role in the variability, or noise, of protein expression. We used mathematical modeling and single-cell reporter assays to show that miRNAs, in conjunction with increased transcription, decrease protein expression noise for lowly expressed genes but increase noise for highly expressed genes. Genes that are regulated by multiple miRNAs show more-pronounced noise reduction. We estimate that hundreds of (lowly expressed) genes in mouse embryonic stem cells have reduced noise due to substantial miRNA regulation. Our findings suggest that miRNAs confer precision to protein expression and thus offer plausible explanations for the commonly observed combinatorial targeting of endogenous genes by multiple miRNAs, as well as the preferential targeting of lowly expressed genes.
authors.affiliation: Integrative Research Institute for the Life Sciences and Institute for Theoretical Biology, Humboldt Universität, 10115 Berlin, Germany. Institute of Pathology, Charité-Universitätsmedizin, 10117 Berlin, Germany. Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge MA 02139, USA.
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Schmiedel
authors.affiliation: Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA.
authors.forename: Sandy L
authors.initials: SL
authors.lastname: Klemm
authors.affiliation: Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge MA 02139, USA.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge MA 02139, USA.
authors.forename: Apratim
authors.initials: A
authors.lastname: Sahay
authors.affiliation: Integrative Research Institute for the Life Sciences and Institute for Theoretical Biology, Humboldt Universität, 10115 Berlin, Germany. Institute of Pathology, Charité-Universitätsmedizin, 10117 Berlin, Germany. nils.bluethgen@charite.de debbie@hms.harvard.edu a.vanoudenaarden@hubrecht.eu.
authors.forename: Nils
authors.initials: N
authors.lastname: Blüthgen
authors.affiliation: Department of Systems Biology, Harvard Medical School, Longwood Avenue, Boston, MA 02115, USA. nils.bluethgen@charite.de debbie@hms.harvard.edu a.vanoudenaarden@hubrecht.eu.
authors.forename: Debora S
authors.initials: DS
authors.lastname: Marks
authors.affiliation: Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge MA 02139, USA. Department of Biology, MIT, Cambridge, MA 02139, USA. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, Netherlands. nils.bluethgen@charite.de debbie@hms.harvard.edu a.vanoudenaarden@hubrecht.eu.
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000502:physiology; D000818:Animals; D053595:Embryonic Stem Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D008957:Models, Genetic; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D059010:Single-Cell Analysis; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; C532375:Mirn20 microRNA, mouse; D012333:RNA, Messenger