Differentiation stage-specific effect of histone deacetylase inhibitors on the expression of RORγT in human lymphocytes.

The role of epigenetic mechanisms in the regulation of the human RORγT gene, which encodes a Th17 lymphocyte signature transcription factor, remains largely unknown. We investigated the effect of histone deacetylase (HDAC) inhibition on RORγT and RORγT-dependent gene expression in human T lymphocytes. We found that, in Jurkat T cells and in in vitro-differentiated Th17 cells, treatment with 2 HDAC inhibitors, butyrate and apicidin, led to the induction of the RORγT gene, which was associated with an increase in histone H4 acetylation near the RORγT proximal promoter. In contrast, when the same inhibitors were added to naive CD4+ cells differentiating in vitro to Th17 cells, they mediated the down-regulation of RORγT expression. In conclusion, HDAC inhibitor-mediated H4 acetylation is involved in the epigenetic regulation of RORγT expression in Th17 cells. However, that epigenetic mechanism was observed only at a specific stage of T cell differentiation, suggesting a complex interaction with additional mechanisms that sequentially regulate RORγT expression. These observations may be relevant to the development of applications for HDAC inhibitors for diseases in which Th17 cells have a role in pathogenic mechanisms, such as some types of cancer or autoimmunologic disorders, to prevent unwanted side effects. © Society for Leukocyte Biology.