title: microRNAs regulate cell-to-cell variability of endogenous target gene expression in developing mouse thymocytes.
abstract: The development and homeostasis of multicellular organisms relies on gene regulation within individual constituent cells. Gene regulatory circuits that increase the robustness of gene expression frequently incorporate microRNAs as post-transcriptional regulators. Computational approaches, synthetic gene circuits and observations in model organisms predict that the co-regulation of microRNAs and their target mRNAs can reduce cell-to-cell variability in the expression of target genes. However, whether microRNAs directly regulate variability of endogenous gene expression remains to be tested in mammalian cells. Here we use quantitative flow cytometry to show that microRNAs impact on cell-to-cell variability of protein expression in developing mouse thymocytes. We find two distinct mechanisms that control variation in the activation-induced expression of the microRNA target CD69. First, the expression of miR-17 and miR-20a, two members of the miR-17-92 cluster, is co-regulated with the target mRNA Cd69 to form an activation-induced incoherent feed-forward loop. Another microRNA, miR-181a, acts at least in part upstream of the target mRNA Cd69 to modulate cellular responses to activation. The ability of microRNAs to render gene expression more uniform across mammalian cell populations may be important for normal development and for disease.
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: Rory
authors.initials: R
authors.lastname: Blevins
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Bruno
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Elliott
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: Antoine
authors.initials: A
authors.lastname: Marcais
authors.affiliation: Department of Microbiology and Immunology and Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Loh
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Hertweck
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max Delbrück Center Berlin, Berlin, Germany.
authors.forename: Azra
authors.initials: A
authors.lastname: Krek
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max Delbrück Center Berlin, Berlin, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.affiliation: Department of Microbiology and Immunology and Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Chang-Zheng
authors.initials: CZ
authors.lastname: Chen
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D060168:Thymocytes / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger