title: Maturation-related histone modifications in the PU.1 promoter regulate Th9-cell development.
abstract: Epigenetic histone modifications are thought to underlie the rapid memory immune response to recall antigen that develops after vaccination. However, histone-modification patterns in genes encoding transcription factors regulating cytokine production have not been investigated in either memory and naive T cells or as the immune system matures to understand the differences in cytokine response patterns. In the present study, we analyzed histone modifications in promoter regions of T-bet, GATA-3, PU.1, IRF4, and RORC in neonatal naive T cells and in adult naive and memory CD4 T cells, and found a unique and dynamic histone-modification pattern in the PU.1 promoter that was related to age and the naive/memory status of a T cell. Naive T cells required more intense stimulation to switch the chromatin pattern in the PU.1 promoter from a repressive to permissive state, and therefore to produce IL-9 than did memory T cells. Inhibition of repressive histone methylation by the specific inhibitor 3-deazaneplanocin induced Th9-specific PU.1 expression, even in conditions that would normally yield only Th0 cytokines. Conversely, prevention of histone acetylation by the histone acetyltransferase inhibitor curcumin diminished PU.1 expression after IL-9-inducing stimulation. Our findings identify age- and differentiation-status-related epigenetic modifications of PU.1 as a unique regulator of Th9 memory acquisition and Th9 immunity.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik IV, University of Munich, Pettenkoferstrasse 8a, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ramming
authors.forename: David
authors.initials: D
authors.lastname: Druzd
authors.forename: Jan
authors.initials: J
authors.lastname: Leipe
authors.forename: Hendrik
authors.initials: H
authors.lastname: Schulze-Koops
authors.forename: Alla
authors.initials: A
authors.lastname: Skapenko
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000276:immunology / Q000502:physiology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D016906:Interleukin-9 / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D016906:Interleukin-9; D008239:Lysine; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C508607:IL9 protein, human