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; Dan R Littman

doi:10.1038/s41467-018-05834-w

Back

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

Journal article

Open access

Peer reviewed

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

Nature communications, Vol.9(1), pp.3594-13

09/05/2018

DOI: 10.1038/s41467-018-05834-w

PMCID: PMC6125341

PMID: 30185805

Files and links (1)

url

https://doi.org/10.1038/s41467-018-05834-wView

Published (Version of record) Open Access

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.

Animals

CD4 Antigens - genetics

CD4 Antigens - metabolism

CD4-Positive T-Lymphocytes - physiology

Cell Differentiation - genetics

Chimera

DNA Demethylation

DNA Methylation - physiology

DNA-Binding Proteins - genetics

DNA-Binding Proteins - metabolism

Enhancer Elements, Genetic - physiology

Epigenesis, Genetic - physiology

Female

Gene Expression Regulation - physiology

Gene Knockout Techniques

Mice

Mice, Inbred C57BL

Mice, Transgenic

Proto-Oncogene Proteins - genetics

Proto-Oncogene Proteins - metabolism

Thymus Gland - cytology

Thymus Gland - physiology

Details

Title: Subtitle: Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development
Creators: Priya D Issuree - New York University
Kenneth Day - HudsonAlpha Institute for Biotechnology
Christy Au - New York University
Ramya Raviram - New York University
Paul Zappile - Genome Technology Center, New York University School of Medicine, New York, NY, 10003, USA.
Jane A Skok - New York University
Hai-Hui Xue - Roy J. and Lucille A. Carver College of Medicine
Richard M Myers - HudsonAlpha Institute for Biotechnology
Dan R Littman - New York University
Resource Type: Journal article
Publication Details: Nature communications, Vol.9(1), pp.3594-13
DOI: 10.1038/s41467-018-05834-w
PMID: 30185805
PMCID: PMC6125341
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: R35 GM122515 / NIGMS NIH HHS
Language: English
Date published: 09/05/2018
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984359936602771

Metrics

11 Record Views

33 Times Cited - Web of Science