Epigenetic and signal transduction contributions of histone deacetylase activity to gene transcription and cell biology. (1) Ligation of cytokine or other inflammatory receptors leads to phosphorylation and/or dimerization of transcription factors (TF), followed by their nuclear translocation and association with histone acetyl transferases (HATs). (2) Subsequent activation of HATs contributes to epigenetic regulation of gene expression through acetylation (Ac) of histones (barrels), relaxing chromatin structure, and (3) exposing gene promoter regions to the TF. Histone deacetylases (HDACs) reverse this epigenetic process, leading to chromatin condensation and repression of gene expression. HATs and HDACs also finely tune gene expression and cellular processes through pleiotropic, nonepigenetic signaling pathways. Sequential acetylation and deacetylation of specific lysine residues on TF – such as signal transducers and activators of transcription (STAT), NFκB p65 and forkhead box class O proteins – in the nucleus or cytoplasm, influence TF protein stability, nuclear localization, DNA binding capacity, activation and gene target specificity. (4) Depending on the transcription factor and gene target, this can either enhance or inhibit gene transcription.