Author:
Padonou Francine,Gonzalez Virginie,Jmari Nada,Maslovskaja Julia,Kisand Kai,Peterson Pärt,Irla Magali,Giraud Matthieu
Abstract
AbstractAire allows medullary thymic epithelial cells (mTECs) to express and present a large number of self-antigens for central tolerance. Although mTECs express a high diversity of self-antigen splice isoforms, the extent and regulation of alternative splicing events (ASEs) included in their transcripts, notably in those induced by Aire, is unknown. Unexpectedly, and in contrast to Aire-neutral genes, we found that the Aire-sensitive genes exhibit in Aire-positive and negative mTECs, a weak inclusion of ASEs, with about a quarter present in peripheral tissues being excluded from the thymus. We identified Raver2, as a splicing-related factor overrepresented in mTECs and dependent on H3K36me3 marks. We discovered that both Raver2 and methylation of H3K36 promoted ASE inclusion for Aire-neutral genes, leaving Aire-sensitive genes unaffected. Profiling of H3K36me3 revealed its depletion at Aire-sensitive genes, supporting a mechanism, whose setup precedes Aire’s expression and by which Aire-sensitive genes exhibit weak ASE inclusion through the escape of Raver2’s effect. Lack of ASEs in Aire-induced transcripts highlights a role for regulatory T cells in controlling the incomplete Aire-dependent negative selection.
Publisher
Cold Spring Harbor Laboratory
Reference49 articles.
1. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development
2. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)
3. Cellular and genetic mechanisms of self tolerance and autoimmunity
4. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia
5. Danan-Gotthold, M. , Guyon, C. , Giraud, M. , Levanon, E. Y. & Abramson, J . Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol. 17, 219 (2016).