Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

Abstract

The ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3end processing complex, suggesting they might impact transcript stability and levels through an effect on 3UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3UTR transcript isoforms in mTECs, a feature preceding Aires expression and correlated with the preferential selection of proximal polyA sites by the 3end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.