An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Central tolerance relies on medullary thymic epithelial cells (TECs) expressing tissue-restricted antigens (TRAs) via promiscuous gene expression (pGE).
• The autoimmune regulator (Aire) protein is a key transcriptional regulator of pGE, but other factors like chromatin configuration and post-transcriptional control also play roles.
• MicroRNAs (miRNAs) are potent post-transcriptional regulators with potential involvement in TEC function and pGE.

Purpose of the Study:

• To investigate the role of miRNAs in regulating pGE within mouse and human TECs.
• To determine the relationship between miRNA expression, Aire, and the control of TRAs in the thymus.

Main Methods:

• Purification of mouse and human TEC subpopulations.
• Microarray profiling to identify miRNA signatures in TECs.
• Analysis of miRNA expression in relation to Aire expression and in Aire knockout models.
• Assessment of pGE in TECs with and without specific miRNAs.

Main Results:

• Identified conserved, cell type- and differentiation-specific miRNA signatures in TECs.
• A subset of miRNAs was upregulated during terminal TEC differentiation and correlated with Aire expression.
• Absence of specific miRNAs in TECs led to reduced Aire expression and impaired pGE for both Aire-dependent and -independent genes.
• Absence of miR-29a specifically impacted Aire-dependent gene expression.

Conclusions:

• Reveals a mutual interdependence between miRNAs and Aire in regulating central tolerance.
• miRNAs are essential for maintaining Aire expression and comprehensive pGE in TECs.
• Highlights miRNAs as critical post-transcriptional regulators in thymic epithelial cell function and immune tolerance induction.