Journal
IMMUNOBIOLOGY
Volume 218, Issue 4, Pages 554-560Publisher
ELSEVIER GMBH
DOI: 10.1016/j.imbio.2012.06.013
Keywords
Autoimmune regulator (Aire); Medullary thymic epithelial cells (mTECs); MicroRNAs (miRNA); Transcription factor-miRNA; Control of miRNA transcription
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Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (Fapesp, Sao Paulo, Brazil)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brasilia, Brazil)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brasilia, Brazil)
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The autoimmune regulator (Aire) is a transcription factor that controls the ectopic expression of a large set of peripheral tissue antigen (PTA) genes in medullary thymic epithelial cells (mTECs). Recent evidence has demonstrated that Aire releases stalled RNA polymerase II (RNA Pol II) from blockage at the promoter region of its target genes. Given that, in addition to messenger RNAs (mRNA), RNA Pol II also transcribes microRNAs (miRNAs), we raised the hypothesis that Aire might play a role as an upstream controller of miRNA transcription. To test this, we initially analyzed the expression profiles of 662 miRNAs in control and Aire-silenced (siRNA) murine mTEC 3.10 cells using microarrays. The bioinformatics programs SAM and Cluster-TreeView were then used to identify the differentially expressed miRNAs and their profiles, respectively. Thirty Aire-dependent miRNAs were identified in the Aire-silenced mTECs, of which 18 were up- and 12 were down-regulated. The down-regulated miR-376 family was the focus of this study because its members (miR-376a, miR-376b and miR-376c) are located,in the genome within the Gm2922 open-reading frame (ORF) gene segment on the chromosome 12F1. The T-boxes (TTATTA) and G-boxes (GATTGG), which represent putative RNA Pol II promoter motifs, were located in a portion spanning 10 kb upstream of the ATG codon of Gm2922. Moreover, we found that Gm2922 encodes an mRNA, which was also down-regulated in Aire-silenced mTECs. These results represent the first evidence that Aire can play a role as a controller of transcription of miRNAs located within genomic regions encompassing ORF and/or mRNA genes. (C) 2012 Elsevier GmbH. All rights reserved.
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