Histone deacetylation inhibits IL4 gene expression in T cells.
BACKGROUND
Dysregulated expression of IL-4 has been linked with allergic diseases. IL-4 expression is controlled at the level of gene transcription by the coordinated action of multiple factors that bind regulatory promoter elements. In addition, alterations in chromatin structure are thought to play a role in regulating the expression of cytokines in the T(H)2 gene cluster, although the biochemical basis for these alterations in human T cells is not well understood.


OBJECTIVE
We sought to define the role of histone acetylation in the regulation of IL4 gene expression in human T cells.


METHODS
IL-4 protein production was measured by means of ELISA. IL-4 promoter activity was measured with luciferase-based reporter constructs transiently transfected into Jurkat T cells. The acetylation status of histones associated with the IL4 gene was analyzed with chromatin immunoprecipitation assays.


RESULTS
IL-4 production from activated peripheral blood T cells was enhanced by the histone deacetylase inhibitor trichostatin A. Overexpression of the type 1 histone deacetylases 1, 2, and 3 inhibited transcription driven by the IL-4 promoter in Jurkat T cells, whereas cotransfection of the histone acetyltransferase CREB-binding protein potentiated IL-4 promoter activity. Using chromatin immunoprecipitation assays, we show that nucleosomes in the proximal IL-4 promoter are acetylated on T-cell activation.


CONCLUSIONS
Our results demonstrate that the acetylation state of histones associated with the IL-4 promoter is a key regulator of IL4 gene expression.
Valapour
Maryam
M
Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA.
Guo
Jia
J
Schroeder
John T
JT
Keen
Judith
J
Cianferoni
Antonella
A
Casolaro
Vincenzo
V
Georas
Steve N
SN
D000107:Acetylation; D050882:CREB-Binding Protein; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D009687:Nuclear Proteins / Q000378:metabolism; D009707:Nucleosomes; D011401:Promoter Regions, Genetic / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D009707:Nucleosomes; D015534:Trans-Activators; D015847:Interleukin-4; C012589:trichostatin A; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D006655:Histone Deacetylases