Understanding immune system development: An epigenetic perspective

Abstract

Since its conception in the 1950s by Waddington and others, the role of epigenetics in various processes such as cellular development, differentiation, metabolism, and disease has been extensively studied. Epigenetic regulation enables a select set of genes to be expressed within each cell during development and differentiation by covalently modifying DNA and histones while keeping the DNA sequence unchanged. Various technical advancements, such as high-speed cell sorting and high-throughput genome-wide analyses of gene expression profiles and occupancy profiles of chromatin-based factors, have led to unraveling of the epigenetic mechanisms regulating immune cell development. In this chapter, we explicate the influence of histone/DNA modifications on chromatin landscape and gene expression. Further, we discuss how spatiotemporal modulation of chromatin accessibility plays a key role toward development and differentiation of various immune cell types, and how only a handful of chromatin-based factors can specifically determine this outcome. We describe the epigenetic regulatory mechanisms orchestrating the development, differentiation, and effector functions of various innate cells including natural killer (NK) cells, macrophages, and dendritic cells (DC) from hematopoietic stem cells (HSCs), followed by B and T adaptive immune cells arising from common lymphoid progenitors (CLPs). We further elaborate how chromatin accessibility is altered during activation and memory formation in these lineages. We also discuss the effect of long-distance or transregulation of gene expression in the context of the immune cells, with focus on Special AT-rich binding protein 1 (SATB1) as the T lineage-enriched global chromatin organizer. Finally, using an example of the TH2 cytokine cluster, we demonstrate how SATB1 integrates higher-order chromatin organization and gene regulation. The ongoing developments in the analysis of epigenetic components and regulatory mechanisms at a single-cell resolution hold great promise in providing novel cues toward understanding the cell type-specific dynamic epigenetic landscape pertaining to each cell state.