Publication: Aire-dependent transcripts escape Raver2-induced splice-event inclusion in the thymic epithelium.

Publié dans: EMBO Rep 2022 Feb; 23(3): e53576

Auteurs: Padonou F, Gonzalez V, Provin N, Yayilkan S, Jmari N, Maslovskaja J, Kisand K, Peterson P, Irla M, Giraud M

Résumé

Aire 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) in their transcripts, notably in those induced by Aire, is unknown. In contrast to Aire-neutral genes, we find that transcripts of Aire-sensitive genes show only a low number of ASEs in mTECs, with about a quarter present in peripheral tissues excluded from the thymus. We identify Raver2, as a splicing-related factor overexpressed in mTECs and dependent on H3K36me3 marks, that promotes ASEs in transcripts of Aire-neutral genes, leaving Aire-sensitive ones unaffected. H3K36me3 profiling reveals its depletion at Aire-sensitive genes and supports a mechanism that is preceding Aire expression leading to transcripts of Aire-sensitive genes with low ASEs that escape Raver2-induced alternative splicing. The lack of ASEs in Aire-induced transcripts would result in an incomplete Aire-dependent negative selection of autoreactive T cells, thus highlighting the need of complementary tolerance mechanisms to prevent activation of these cells in the periphery.

Lien vers Pubmed [PMID] – 35037357

Lien vers le DOI – 10.15252/embr.202153576