Coordinated histone H3 methylation and acetylation regulate physiologic and pathologic fas ligand gene expression in human CD4+ T cells

J Immunol. 2014 Jul 1;193(1):412-21. doi: 10.4049/jimmunol.1400055. Epub 2014 Jun 4.


Activation-induced Fas ligand (FasL) mRNA expression in CD4+ T cells is mainly controlled at transcriptional initiation. To elucidate the epigenetic mechanisms regulating physiologic and pathologic FasL transcription, TCR stimulation-responsive promoter histone modifications in normal and alcohol-exposed primary human CD4+ T cells were examined. TCR stimulation of normal and alcohol-exposed cells led to discernible changes in promoter histone H3 lysine trimethylation, as documented by an increase in the levels of transcriptionally permissive histone 3 lysine 4 trimethylation and a concomitant decrease in the repressive histone 3 lysine 9 trimethylation. Moreover, acetylation of histone 3 lysine 9 (H3K9), a critical feature of the active promoter state that is opposed by histone 3 lysine 9 trimethylation, was significantly increased and was essentially mediated by the p300-histone acetyltransferase. Notably, the degree of these coordinated histone modifications and subsequent recruitment of transcription factors and RNA polymerase II were significantly enhanced in alcohol-exposed CD4+ T cells and were commensurate with the pathologic increase in the levels of FasL mRNA. The clinical relevance of these findings is further supported by CD4+ T cells obtained from individuals with a history of heavy alcohol consumption, which demonstrate significantly greater p300-dependent H3K9 acetylation and FasL expression. Overall, these data show that, in human CD4+ T cells, TCR stimulation induces a distinct promoter histone profile involving a coordinated cross-talk between histone 3 lysine 4 and H3K9 methylation and acetylation that dictates the transcriptional activation of FasL under physiologic, as well as pathologic, conditions of alcohol exposure.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alcohol Drinking / adverse effects
  • Alcohol Drinking / immunology*
  • Alcohol Drinking / pathology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Fas Ligand Protein / immunology*
  • Female
  • Gene Expression Regulation / immunology*
  • Histones / immunology*
  • Humans
  • Male
  • Methylation
  • Receptors, Antigen, T-Cell / immunology*
  • p300-CBP Transcription Factors / immunology


  • FASLG protein, human
  • Fas Ligand Protein
  • Histones
  • Receptors, Antigen, T-Cell
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor