CD8 + T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections

Abstract

Differentiation of effector and memory CD8+ T cells is accompanied by extensive changes in the transcriptome and histone modifications at gene promoters; however, the enhancer repertoire and associated gene regulatory networks are poorly defined. Using histone mark chromatin immunoprecipitation coupled with deep sequencing, we mapped the enhancer and super-enhancer landscapes in antigen-specific naïve, differentiated effector, and central memory CD8+ T cells during LCMV infection. Epigenomics-based annotation revealed a highly dynamic repertoire of enhancers, which were inherited, de novo activated, decommissioned and re-activated during CD8+ T cell responses. We employed a computational algorithm to pair enhancers with target gene promoters. On average, each enhancer targeted three promoters and each promoter was regulated by two enhancers. By identifying enriched transcription factor motifs in enhancers, we defined transcriptional regulatory circuitries at each CD8+ T-cell response stage. These multi-dimensional datasets provide a blueprint for delineating molecular mechanisms underlying functional differentiation of CD8+ T cells.

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

“…The rationale for investigating the enhancer region of the PRF1 gene relies on the fact that the regulation by enhancers are proven to be highly dynamic upon CD8 + T cell activation and differentiation [24]. Furthermore, the transcription of PRF1 is regulated mainly by the enhancer located at position –1kb from the TSS, which has binding sites for transcription factors related to T cell activation, such as signal transducer and activator of transcription (STAT)‐5, nuclear factor kappa B (NF‐κB) and activator protein 1 (AP‐1) [25].…”

Developmental Origin Governs CD8+ T Cell Fate Decisions during Infection

“…Transcription factors (TFs) regulate differentiation of CD8 + T cells (Kaech and Cui, 2012;White et al, 2017) by binding regulatory motifs in open enhancers and promoters (He et al, 2016;Scharer et al, 2017;Yu et al, 2017). To identify TFs that determine the fates of CD8 + T cells produced at different ages, we calculated the enrichment of TF binding motifs in loci that exhibited differential chromatin accessibility among 1d ts VM, 28d ts VM, or 28d ts TN cells.…”

Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity

“…Treatment of effector or memory T cells subsets with histone acetylase or deacetylase inhibitors modulates expression of effector-associated molecules (Araki, Wang, et al 2009) and affects memory function and potential (Northrop, Wells, and Shen 2008), further emphasizing a role for epigenetic changes in regulating gene expression at different stages of the T cell response (Figure 1A). Recent studies of antigen-specific CD8 + T cells expand these analyses, including genome-wide assessment of histone modification of H3K4me1 and H3K27ac marks (He et al 2016) as well as ATAC-seq (Yu et al 2017), to show extensive remodeling of enhancers as the effector and memory populations differentiate and, along with improved computational approaches, predict TF binding activity at each differentiation state with greater resolution. Of more than 50,000 enhancers identified, approximately 50% were unchanged over the course of the immune response.…”