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. 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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Maturation-related Histone Modifications in the PU.1 Promoter Regulate Th9-cell Development

Andreas Ramming et al. Blood. .

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.

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