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

Priya D. Issuree, Kenneth Day, Christy Au, Ramya Raviram, Paul Zappile, Jane A. Skok, Hai-Hui Xue, Richard M. Myers and Dan R. Littman ()
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Priya D. Issuree: New York University School of Medicine
Kenneth Day: Hudson Alpha Institute for Biotechnology
Christy Au: New York University School of Medicine
Ramya Raviram: New York University School of Medicine
Paul Zappile: New York University School of Medicine
Jane A. Skok: New York University School of Medicine
Hai-Hui Xue: University of Iowa
Richard M. Myers: Hudson Alpha Institute for Biotechnology
Dan R. Littman: New York University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05834-w

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