CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element.

Teghanemt, Athmane; Pulipati, Priyanjali; Misel-Wuchter, Kara; Day, Kenneth; Yorek, Matthew S.; Yi, Ren; Keen, Henry L.; Au, Christy; Maretzky, Thorsten; Gurung, Prajwal; Littman, Dan R.; Issuree, Priya D.

The epigenetic patterns that are established during early thymic development might determine mature T cell physiology and function, but the molecular basis and topography of the genetic elements involved are not fully known. Here we show, using the Cd4 locus as a paradigm for early developmental programming, that DNA demethylation during thymic development licenses a novel stimulus-responsive element that is critical for the maintenance of Cd4 gene expression in effector T cells. We document the importance of maintaining high CD4 expression during parasitic infection and show that by driving transcription, this stimulus-responsive element allows for the maintenance of histone H3K4me3 levels during T cell replication, which is critical for preventing de novo DNA methylation at the Cd4 promoter. A failure to undergo epigenetic programming during development leads to gene silencing during effector T cell replication. Our study thus provides evidence of early developmental events shaping the functional fitness of mature effector T cells. Epigenetic states that are established during thymic T cell development influence functionality of mature T cells. Authors here show that early developmental programming of the Cd4 locus is comprised of DNA-demethylation at a specific stimulus-responsive element, which allows long-term maintenance of activator histone H3K4 trimethylation and transcription.

DNA demethylation; T cells; CD4 antigen; GENE silencing; PARASITIC diseases; HISTONES; CELL physiology

Nature Communications, 2022, Vol 13, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-022-28914-4