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

Authors: Ghare, Smita S; Joshi-Barve, Swati; Moghe, Akshata; Patil, Madhuvanti; Barker, David F; Gobejishvili, Leila; Brock, Guy N; Cave, Matthew; McClain, Craig J; Barve, Shirish S

Published In J Immunol, (2014 Jul 01)

Abstract: 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.

PubMed ID: 24899502

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