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MicroRNAs (miRNAs) are small endogenous RNA molecules that regulate gene expression by base-pairing with target messenger RNAs (mRNAs), leading to mRNA degradation or translational repression. As a result, miRNAs control protein concentration at post-transcriptional and translational levels, but do not affect mRNA transcription or protein stability. Several thousand miRNAs have been identified in organisms as diverse as viruses, worms or mammals, and it is currently predicted that 10-30% of genes in humans might be regulated by miRNAs.
During the course of immune responses, lymphocytes must respond rapidly to antigenic stimulation by initiating complex changes in gene expression that allow differentiation into effector and memory cells. These events lead to the production of high affinity antibodies and development of lasting immunological protection which underpins effective vaccination. Understanding lymphocyte function is therefore relevant not only for improving health, but also for treatment of diseases, as aberrant lymphocyte function can lead to autoimmunity or cancer.
Our previous work has implicated a particular miRNA, miR-155, as being required for lymphocyte function (Science, 2007). Further studies in our laboratory have revealed that miR-155 is required for the production of high affinity antibodies by B cells. We have identified potential target genes of miR155, abnormal expression of which may contribute to the B and T cell phenotypes. This knowledge may also be relevant for cancer biology as over-expression of miR-155 leads to B cell transformation. Only by understanding the normal biological processes regulated by miRNAs and their network of target genes will it be possible to safely unlock their full potential for pharmaceutical intervention in the treatment of human diseases.
Torres AG, Fabani MM, Vigorito E, Gait MJ (2011) MicroRNA fate upon targeting with anti-miRNA oligonucleotides as revealed by an improved Northern-blot-based method for miRNA detection.
RNA 17 933-943
Fabani MM, Abreu-Goodger C, Williams D, Lyons PA, Torres AG, Smith KGC, Enright AJ, Gait MJ, Vigorito E (2010) Efficient inhibition of miR-155 function in vivo by peptide nucleic acids.
Nucleic Acids Research 38 4466-4475
Capasso M, Bhamrah MK, Henley T, Boyd RS, Langlais C, Cain K, Dinsdale D, Pulford K, Khan M, Musset B, Cherny VV, Morgan D, Gascoyne RD, Vigorito E, DeCoursey TE, MacLennan ICM, Dyer MJS (2010) HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species.
Nature Immunology 11 265-272
Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E (2009) Cutting Edge: The Foxp3 target miR-155 contributes to the development of regulatory T cells.
Journal of Immunology 182 2578-2582
Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, Kohlhaas S, Das PP, Miska EA, Rodriguez A, Bradley A, Smith KGC, Rada C, Enright AJ, Toellner K-M, MacLennan ICM, Turner M (2007) microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells.
Immunity 27 847-859
Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M, Bradley A (2007) Requirement of bic/microRNA-155 for normal immune function.
Science 316 608-611
Vigorito E, Turner M (2006) Differential requirements of PI3K subunits for BCR or BCR/CD19-induced ERK activation.
Advances in Experimental Medicine and Biology 584 43-52
Philipp Staudacher - PhD student
Rebecca Leyland - Post-doctoral scientist
Dong Lu - Post-doctoral scientist
Babraham Institute - Babraham Research Campus - Cambridge - United Kingdom