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Nat Commun. 2018 Sep 5;9(1):3594. doi: 10.1038/s41467-018-05834-w.

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

Author information

1
The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, 10016, USA.
2
Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA.
3
Intermountain Precision Genomics, Translational Science Center, 292 S 1470 E Suite 201, St George, UT, 84790, USA.
4
Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, 10016, USA.
5
Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA.
6
Genome Technology Center, New York University School of Medicine, New York, NY, 10003, USA.
7
Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
8
The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, 10016, USA. dan.littman@med.nyu.edu.
9
Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, 10016, USA. dan.littman@med.nyu.edu.
10
Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA. dan.littman@med.nyu.edu.

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.

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