The role of miRNAs in pGE and TEC biology

Scientists

Kaiyong Li and Olga Ucar

Project

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MicroRNAs (miRNAs) are small RNA molecules involved in the post-transcriptional control of gene expression. Mature miRNAs bind Argonaute proteins and are incorporated into the RNA-induced silencing complex (RISC), which in turn binds to the target mRNA leading to translational block and/or degradation. A primary miRNA transcript is first processed by Drosha in the nucleus and then by Dicer in the cytoplasm. Inactivation of either of these two enzymes blocks the biogenesis of mature miRNAs. Various miRNAs have been shown to play important roles in development, cellular homeostasis and pathological conditions. Several autoimmune diseases are associated with aberrant miRNA expression, which presumably leads to hyperactivation of immune effector cells.

Given the involvement of miRNAs as potent post-transcriptional regulators in developmental switches, lineage commitment and gene expression regulation, we investigated their role in the thymic epithelium development and maintenance and the molecular regulation of pGE. Genetic deletion of Dicer (and therefore all mature miRNAs) in TECs results in premature thymic involution, progressive disorganisation of the thymic epithelium and formation of epithelial voids (1). The epithelial defects manifest around weaning, and the ensuing decrease of the thymic T-cell export leads to an increased susceptibility to collagen-induced autoimmune arthritis (1).

MTECs can be subdivided into distinct maturation stages according to the surface expression of CD80 and MHCII (2). Immature CD80lowMHCIIlow mTECs continuously give rise to mature CD80highMHCIIhigh cells thus leading to a rapid turnover of mTECs (2). Although embryonic thymic epithelial progenitors have been studied in some detail, little is known about the developmental hierarchy and turnover rate of such progenitors in the adult thymus. We identified distinct subsets within immature mTECs, the distribution of which is affected in Dicer mutants. The progression towards the final maturation stage (CD80highMHCIIhigh) is also disrupted in the absence of mature miRNAs in the thymic epithelium (3). We are currently investigating the role of various miRNAs in the mTEC lineage progression and thymic epithelium turnover.

Microarray profiling of TEC subpopulations revealed cell type- and differentiation-specific miRNA signatures, with a subset of miRNAs being significantly upregulated during terminal mTEC differentiation (3). The differential regulation of this subset of miRNAs and Aire was correlated during terminal mTEC differentiation and some of these miRNAs were mis-expressed in the Aire knockout thymus. In turn, the specific absence of miRNAs in TECs resulted in a progressive reduction of Aire expression and pGE, affecting both Aire-dependent and -independent genes (3). The role of evolutionarily conserved TEC-specific miRNAs in the molecular control of pGE is currently studied.

Selected publications

1. Papadopoulou, A.S., J. Dooley, M.A. Linterman, W. Pierson, O. Ucar, B. Kyewski, S. Zuklys, G.A. Hollander, P. Matthys, D.H.D. Gray, B. De Strooper, and A. Liston. 2011. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a-mediated suppression of interferon alpha receptor . Nat. Immunol. 13:181-187.

2. Gäbler, J., J. Arnold, and B. Kyewski. 2007. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells.Eur. J. Immunol. 37, 3363-3372.

3. Ucar, O., L.-O. Tykocinski, J. Dooley, A. Liston, and B. Kyewski. 2013. An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression. Eur. J. Immunol. 43: 1769-1778.

4. Ucar, O. and K. Rattay. 2015. Promiscuous gene expression in the thymus: a matter of epigenetics, miRNA, and more? Frontiers in Immunol. 6: 93.

 

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