3D Chromatin Dynamics during Innate and Adaptive Immune Memory Acquisition

Abstract

Immune cells responding to pathogens undergo molecular changes that are intimately linked to genome organization. Recent work has demonstrated that natural killer (NK) and CD8+ T cells experience substantial transcriptomic and epigenetic rewiring during their differentiation from naive to effector to memory cells. Whether these molecular adaptations are accompanied by changes in three-dimensional (3D) chromatin architecture is unknown. In this study, we combine histone profiling, ATAC-seq, RNA-seq and high-throughput chromatin capture (HiC) assay to investigate the dynamics of one-dimensional (1D) and 3D chromatin during the differentiation of innate and adaptive lymphocytes. To this end, we discovered a coordinated 1D and 3D epigenetic remodeling during innate immune memory differentiation, and demonstrate that effector CD8+ T cells adopt an NK-like architectural program that is maintained in memory cells. Altogether, our study reveals the dynamic nature of the 1D and 3D genome during the formation of innate and adaptive immunological memory.

Extrinsic and intrinsic drivers of natural killer cell clonality

“…66 In general, memory NK cells in mice and humans show pronounced transcriptional and epigenetic remodeling, distinguishing them globally from their conventional counterparts. 9,65,[67][68][69][70] As will be discussed below, activation by the pro-inflammatory cytokines IL-12 and IL-18 plays an important role in this remodeling, which in combination with IL-15 can recapitulate many aspects of the CMVinduced remodeling in vitro. 64,67 Accordingly, a large fraction of remodeled chromatin regions is bound by the IL-12-induced transcription factor (TF) STAT4, and its genetic deletion disrupts the epigenetic remodeling during MCMV infection.…”

“…In general, memory NK cells in mice and humans show pronounced transcriptional and epigenetic remodeling, distinguishing them globally from their conventional counterparts 9,65,67–70 . As will be discussed below, activation by the pro‐inflammatory cytokines IL‐12 and IL‐18 plays an important role in this remodeling, which in combination with IL‐15 can recapitulate many aspects of the CMV‐induced remodeling in vitro 64,67 .…”

Whole Genome 3D Blood Biopsy Profiling of Canine Cancers: Development and Validation of EpiSwitch Multi-Choice Array-Based Diagnostic Test

“…These extracellular vesicles, with their cargoes of metabolites, nucleic acids, non-coding RNA, lipids, and peptides transfer horizontally from cells of origin to recipient cells and result in the modulation of immune cells (representing systemic changes), as well as modulation of secondary sites. Together this generates systemic epigenetic synchronization and changes in 3D genomic profiles, detectable by the EpiSwitch microarray platform 66–69 . Here we have deployed the stratifying capabilities of the whole genome EpiSwitch 3D genomic array profiling based on peripheral blood biopsy to several prevalent canine cancers: lymphomas – DLBCL and TZL; HSA, histiocytic sarcoma, osteosarcoma; and canine malignant melanoma.…”

“…These extracellular vesicles, with their cargoes of metabolites, nucleic acids, non-coding RNA, lipids, and peptides transfer horizontally from cells of origin to recipient cells and result in the modulation of immune cells (representing systemic changes), as well as modulation of secondary sites. Together this generates systemic epigenetic synchronization and changes in 3D genomic profiles, detectable by the EpiSwitch microarray platform [66][67][68][69] .…”

Vorinostat-induced acetylation of RUNX3 reshapes transcriptional profile through long-range enhancer-promoter interactions in natural killer cells

“…Enhancers are often located far from their target genes, and three-dimensional (3D) genome structure provides a mechanism to precisely regulate gene expression. The action range of enhancers is restricted by topologically associating domain (TAD) boundaries; intra-TAD chromatin looping facilitates the interaction of distal enhancers with their target promoters ( 13 , 14 ).…”