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Immunity. 2016 Dec 20;45(6):1341-1354. doi: 10.1016/j.immuni.2016.11.009. Epub 2016 Dec 13.

CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections.

Author information

1
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
2
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
3
Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
4
Illumina Inc., San Diego, CA 92122, USA.
5
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, IA 52242, USA.
6
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, IA 52242, USA.
7
State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, P.R. China 100193.
8
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: tank1@email.chop.edu.
9
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, IA 52242, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: hai-hui-xue@uiowa.edu.

Abstract

Differentiation of effector and memory CD8+ T cells is accompanied by extensive changes in the transcriptome and histone modifications at gene promoters; however, the enhancer repertoire and associated gene regulatory networks are poorly defined. Using histone mark chromatin immunoprecipitation coupled with deep sequencing, we mapped the enhancer and super-enhancer landscapes in antigen-specific naive, differentiated effector, and central memory CD8+ T cells during LCMV infection. Epigenomics-based annotation revealed a highly dynamic repertoire of enhancers, which were inherited, de novo activated, decommissioned and re-activated during CD8+ T cell responses. We employed a computational algorithm to pair enhancers with target gene promoters. On average, each enhancer targeted three promoters and each promoter was regulated by two enhancers. By identifying enriched transcription factor motifs in enhancers, we defined transcriptional regulatory circuitry at each CD8+ T cell response stage. These multi-dimensional datasets provide a blueprint for delineating molecular mechanisms underlying functional differentiation of CD8+ T cells.

KEYWORDS:

CD8 T cells; Central memory; Effector CD8 T cells; Enhancer-promoter interactome; Enhancers; Epigenetics; Hi-C; Naïve CD8 T cells; Super enhancers; Transcriptional regulatory network

PMID:
27986453
PMCID:
PMC5304416
[Available on 2017-12-20]
DOI:
10.1016/j.immuni.2016.11.009
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