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Blood. 2012 May 17;119(20):4665-74. doi: 10.1182/blood-2011-11-392589. Epub 2012 Mar 23.

Maturation-related histone modifications in the PU.1 promoter regulate Th9-cell development.

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Division of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik IV, University of Munich, Pettenkoferstrasse 8a, Munich, Germany.


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.

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