title: Coordinated histone H3 methylation and acetylation regulate physiologic and pathologic fas ligand gene expression in human CD4+ T cells.
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.
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202;
authors.forename: Smita S
authors.initials: SS
authors.lastname: Ghare
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202; and.
authors.forename: Swati
authors.initials: S
authors.lastname: Joshi-Barve
authors.affiliation: University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202; and.
authors.forename: Akshata
authors.initials: A
authors.lastname: Moghe
authors.affiliation: University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202; and.
authors.forename: Madhuvanti
authors.initials: M
authors.lastname: Patil
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202;
authors.forename: David F
authors.initials: DF
authors.lastname: Barker
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202;
authors.forename: Leila
authors.initials: L
authors.lastname: Gobejishvili
authors.affiliation: Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY 40202.
authors.forename: Guy N
authors.initials: GN
authors.lastname: Brock
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202; and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cave
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202; and.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202; and shirishbarve@gmail.com.
authors.forename: Shirish S
authors.initials: SS
authors.lastname: Barve
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D053222:Fas Ligand Protein / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006657:Histones / Q000276:immunology*; D006801:Humans; D008297:Male; D008745:Methylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D050880:p300-CBP Transcription Factors / Q000276:immunology; D000099224:p300-CBP-Associated Factor
chemical_list: D053222:Fas Ligand Protein; D006657:Histones; D011948:Receptors, Antigen, T-Cell; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C505661:FASLG protein, human