title: Epigenetic Networks Regulate the Transcriptional Program in Memory and Terminally Differentiated CD8+ T Cells.
abstract: Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8+T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8+T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8+T cell maintenance and T cell terminal differentiation.
authors.affiliation: Department of Immunology, Central University Hospital of Asturias, 33011 Oviedo, Spain.
authors.forename: Ramon M
authors.initials: RM
authors.lastname: Rodriguez
authors.affiliation: Department of Immunology, Central University Hospital of Asturias, 33011 Oviedo, Spain.
authors.forename: Beatriz
authors.identifier: 0000-0002-3431-4206
authors.initials: B
authors.lastname: Suarez-Alvarez
authors.affiliation: Genome Analysis Platform, CIC bioGUNE and CIBERehd, Technological Park of Bizkaia, 48160 Derio, Spain.
authors.forename: José L
authors.identifier: 0000-0003-0914-3211
authors.initials: JL
authors.lastname: Lavín
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215; and.
authors.forename: David
authors.initials: D
authors.lastname: Mosén-Ansorena
authors.affiliation: Department of Immunology, Central University Hospital of Asturias, 33011 Oviedo, Spain.
authors.forename: Aroa
authors.initials: A
authors.lastname: Baragaño Raneros
authors.affiliation: Department of Immunology, Central University Hospital of Asturias, 33011 Oviedo, Spain.
authors.forename: Leonardo
authors.identifier: 0000-0002-5019-5753
authors.initials: L
authors.lastname: Márquez-Kisinousky
authors.affiliation: Genome Analysis Platform, CIC bioGUNE and CIBERehd, Technological Park of Bizkaia, 48160 Derio, Spain.
authors.forename: Ana M
authors.identifier: 0000-0002-8271-612X
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: Department of Immunology, Central University Hospital of Asturias, 33011 Oviedo, Spain; inmuno@hca.es.|Fundación Renal Íñigo Álvarez de Toledo, 28003 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Larrea
mesh_terms: D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic; D059467:Transcriptome