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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / physiology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Epigenesis, Genetic / immunology
  • Epigenesis, Genetic / physiology
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histone-Lysine N-Methyltransferase / physiology
  • Histones / metabolism*
  • Humans
  • Infant, Newborn
  • Interleukin-9 / metabolism*
  • Lysine / metabolism
  • Methylation
  • Promoter Regions, Genetic / physiology
  • Protein Processing, Post-Translational / physiology
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • T-Lymphocytes, Helper-Inducer / metabolism
  • T-Lymphocytes, Helper-Inducer / physiology*
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Trans-Activators / physiology


  • Histones
  • IL9 protein, human
  • Interleukin-9
  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Lysine