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

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

Nat Commun. 2018 09 05;9(1):3594

Authors: Issuree PD, Day K, Au C, Raviram R, Zappile P, Skok JA, Xue HH, Myers RM, Littman DR

Abstract
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.

PMID: 30185805 [PubMed – indexed for MEDLINE]