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      Promiscuous Gene Expression in the Thymus: A Matter of Epigenetics, miRNA, and More?

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          Abstract

          The induction of central tolerance in the course of T cell development crucially depends on promiscuous gene expression (pGE) in medullary thymic epithelial cells (mTECs). mTECs express a genome-wide variety of tissue-restricted antigens (TRAs), preventing the escape of autoreactive T cells to the periphery, and the development of severe autoimmunity. Most of our knowledge of how pGE is controlled comes from studies on the autoimmune regulator (Aire). Aire activates the expression of a large subset of TRAs by interacting with the general transcriptional machinery and promoting transcript elongation. However, further factors regulating Aire-independent TRAs must be at play. Recent studies demonstrated that pGE in general and the function of Aire in particular are controlled by epigenetic and post-transcriptional mechanisms. This mini-review summarizes current knowledge of the regulation of pGE by miRNA and epigenetic regulatory mechanisms such as DNA methylation, histone modifications, and chromosomal topology.

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          Most cited references56

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          Projection of an immunological self shadow within the thymus by the aire protein.

          Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.
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            Diversifying microRNA sequence and function.

            MicroRNAs (miRNAs) regulate the expression of most genes in animals, but we are only now beginning to understand how they are generated, assembled into functional complexes and destroyed. Various mechanisms have now been identified that regulate miRNA stability and that diversify miRNA sequences to create distinct isoforms. The production of different isoforms of individual miRNAs in specific cells and tissues may have broader implications for miRNA-mediated gene expression control. Rigorously testing the many discrepant models for how miRNAs function using quantitative biochemical measurements made in vivo and in vitro remains a major challenge for the future.
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              MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation.

              MicroRNAs (miRNAs) are small RNAs that function as posttranscriptional regulators of gene expression. miRNAs affect a variety of signaling pathways, and impaired miRNA regulation may contribute to the development of cancer and other diseases. Here we show that miRNA miR-10a interacts with the 5' untranslated region of mRNAs encoding ribosomal proteins to enhance their translation. miR-10a alleviates translational repression of the ribosomal protein mRNAs during amino acid starvation and is required for their translational induction following anisomycin treatment or overexpression of RAS. We show that miR-10a binds immediately downstream of the regulatory 5'TOP motif and that the 5'TOP regulatory complex and miR-10a are functionally interconnected. The results show that miR-10a may positively control global protein synthesis via the stimulation of ribosomal protein mRNA translation and ribosome biogenesis and hereby affect the ability of cells to undergo transformation.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                03 March 2015
                2015
                : 6
                : 93
                Affiliations
                [1] 1Division of Developmental Immunology, German Cancer Research Center , Heidelberg, Germany
                Author notes

                Edited by: Geraldo Aleixo Passos, University of São Paulo, Brazil

                Reviewed by: Mitsuru Matsumoto, University of Tokushima, Japan; Mireia Guerau-de-Arellano, The Ohio State University, USA

                *Correspondence: Olga Ucar, Division of Developmental Immunology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69126, Germany e-mail: o.ucar@ 123456dkfz.de

                This article was submitted to Immunological Tolerance, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2015.00093
                4347492
                25784915
                8c903b9d-92a7-4dc8-afea-8f0c1cfed2c3
                Copyright © 2015 Ucar and Rattay.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 December 2014
                : 17 February 2015
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 72, Pages: 7, Words: 5800
                Funding
                Funded by: German Cancer Research Center
                Funded by: European Research Council
                Award ID: ERC-2012-AdG
                Categories
                Immunology
                Mini Review

                Immunology
                mtec,promiscuous gene expression,aire,epigenetic,mirna,tolerance,tissue-restricted antigen
                Immunology
                mtec, promiscuous gene expression, aire, epigenetic, mirna, tolerance, tissue-restricted antigen

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