Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development.

Issuree, Priya D.; Day, Kenneth; Au, Christy; Ramya Raviram; Zappile, Paul; Skok, Jane A.; Hai-Hui Xue; Myers, Richard M.; Littman, Dan R.

The inheritance of gene expression patterns is dependent on epigenetic regulation, but the establishment and maintenance of epigenetic landscapes during T cell differentiation are incompletely understood. Here we show that two stage-specific Cd4 cis-elements, the previously characterized enhancer E4p and a novel enhancer E4m, coordinately promote Cd4 transcription in mature thymic MHC-II-specific T cells, in part through the canonical Wnt pathway. Specifically, E4p licenses E4m to orchestrate DNA demethylation by TET1 and TET3, which in turn poises the Cd4 locus for transcription in peripheral T cells. Cd4 locus demethylation is important for subsequent Cd4 transcription in activated peripheral T cells wherein these cis-elements become dispensable. By contrast, in developing thymocytes the loss of TET1/3 does not affect Cd4 transcription, highlighting an uncoupled event between transcription and epigenetic modifications. Together our findings reveal an important function for thymic cis-elements in governing gene expression in the periphery via a heritable epigenetic mechanism.

Nature Communications, 2018, p1

2041-1723

Academic Journal

10.1038/s41467-018-05834-w