Cbf?2 controls differentiation of and confers homing capacity to prethymic progenitors.

ABSTRACT: Multipotent hematopoietic progenitors must acquire thymus-homing capacity to initiate T lymphocyte development. Despite its importance, the transcriptional program underlying this process remains elusive. Cbf? forms transcription factor complexes with Runx proteins, and here we show that Cbf?2, encoded by an RNA splice variant of the Cbfb gene, is essential for extrathymic differentiation of T cell progenitors. Furthermore, Cbf?2 endows extrathymic progenitors with thymus-homing capacity by inducing expression of the principal thymus-homing receptor, Ccr9. This occurs via direct binding of Cbf?2 to cell type-specific enhancers, as is observed in Ror?t induction during differentiation of lymphoid tissue inducer cells by activation of an intronic enhancer. As in mice, an alternative splicing event in zebrafish generates a Cbf?2-specific mRNA, important for ccr9 expression. Thus, despite phylogenetically and ontogenetically variable sites of origin of T cell progenitors, their robust thymus-homing capacity is ensured by an evolutionarily conserved mechanism emerging from functional diversification of Runx transcription factor complexes by acquisition of a novel splice variant.

SUBMITTER: Tenno M 

PROVIDER: S-EPMC5789415 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature