Rapid recall ability of memory T cells is associated with epigenetic gene poising (P1134)

Abstract

Abstract While association of histone modifications with expressed or silent genes has been established, it remains unclear how changes in chromatin environment relate to changes in gene expression. We used ChIP-Seq to analyze the genome-wide changes in chromatin modifications during short-term activation of total human CD4+ T cells by T cell receptor (TCR) signaling. In resting and activated T cells, expressed genes were strongly associated with “active” modifications (e.g. H3K4me1/2/3, H2A.Z) and RNA Polymerase II (Pol II), while silent genes were typically associated with repressive marks. However, we found that about 20-30% of silent genes were poised - they possessed positive modifications and sometimes even Pol II at their promoters. Interestingly, majority of genes induced during T cell activation were poised in resting cells even before the TCR signaling was initiated. Similarly, genes that were silenced upon T cell activation retained active chromatin modifications even after being silenced. This suggested that poising might result from memory of past transcription. We next proceeded to compare histone modification profiles of naïve and memory T cells and discovered that ability of memory cells to produce characteristic cytokines is correlated with the presence of poising marks at the enhancers and promoters of these genes. This led us to propose a model of T cell memory in which immunological memory state is determined epigenetically - by transcriptional memory and poising.