The role of p300‐HAT in promoter‐associated histone acetylation and regulation of FasL gene expression in ethanol treated CD4+ T lymphocytes

Abstract

Alcohol abuse is known to induce immunosuppression by depleting CD4+ T cells. We have shown that ethanol decreases S‐adenosylmethionine levels and enhances activation induced cell death (AICD) in CD4+ T cells. The Fas‐FasL system plays a major role in AICD of T cells. Increased FasL gene expression has been seen in HIV infection and cancer. Histone acetylation maintained by histone acetyltransferases (HATs) and histone deacetylases (HDACs) are important for transcription. p300 is a transcriptional co‐activator with intrinsic HAT activity and is directly involved in chromatin remodeling. Accordingly, we investigated the immunotoxic effects of ethanol by examining FasL promoter histone modifications in the regulation of FasL gene expression in CD4+ T cells. FasL promoter ChIP analysis in ethanol treated T cells showed increase in histone H3 acetylation which is associated with active transcription. In correspondence with increased acetylation, ethanol was observed to enhance the recruitment of p300 and relevant transcription factors which correlated with increased FasL expression. Notably, garcinol, a specific p300‐ HAT inhibitor markedly reduced p300 targeting, histone acetylation and FasL gene expression. Overall these data identify the role of ethanol‐mediated p300 targeting and resultant histone acetylation as a critical mechanism for ethanol‐induced FasL mediated AICD in CD4+ T cells.