title: CD8+T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections.
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.
authors.affiliation: 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.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Xing
authors.affiliation: Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Changya
authors.initials: C
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: Illumina Inc., San Diego, CA 92122, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Teng
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shan
authors.affiliation: 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.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Gullicksrud
authors.affiliation: 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.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Martin
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, P.R. China 100193.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
authors.affiliation: 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.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Badovinac
authors.affiliation: 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.
authors.forename: Kai
authors.initials: K
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Xue
mesh_terms: D000465:Algorithms; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000276:immunology*; D057890:Epigenomics / Q000379:methods; D005786:Gene Expression Regulation / Q000276:immunology*; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology
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