Multi-Dimensional Gene Regulation in Innate and Adaptive Lymphocytes: A View From Regulomes

Abstract

The precise control of cytokine production by innate lymphoid cells (ILCs) and their T cell adaptive system counterparts is critical to mounting a proper host defense immune response without inducing collateral damage and autoimmunity. Unlike T cells that differentiate into functionally divergent subsets upon antigen recognition, ILCs are developmentally programmed to rapidly respond to environmental signals in a polarized manner, without the need of T cell receptor (TCR) signaling. The specification of cytokine production relies on dynamic regulation of cis-regulatory elements that involve multi-dimensional epigenetic mechanisms, including DNA methylation, transcription factor binding, histone modification and DNA-DNA interactions that form chromatin loops. How these different layers of gene regulation coordinate with each other to fine tune cytokine production, and whether ILCs and their T cell analogs utilize the same regulatory strategy, remain largely unknown. Herein, we review the molecular mechanisms that underlie cell identity and functionality of helper T cells and ILCs, focusing on networks of transcription factors and cis-regulatory elements. We discuss how higher-order chromatin architecture orchestrates these components to construct lineage- and state-specific regulomes that support ordered immunoregulation.

Keywords: ATAC-seq and chromatin accessibility; de novo enhancers; histone modifications; innate lymphoid cell (ILC); lineage-determining transcription factors; poised enhancers; signal-regulated transcription factors.

Figure 1

Dynamics of NK cell regulomes during infection. (A) Dynamic regulomes during infection. Innate immune response occurs along with changes in gene expression as well as chromatin accessibility. (B) High-magnitude gene upregulation during NK cell activation relies on recruitment of signal-regulated transcription factors (SRTFs) to poised enhancers that are developmentally acquired in a lineage-determining transcription factors (LDTFs) manner for chromatin remodeling (top) (72). High-magnitude gene induction also forms de novo enhancers through a process involving sequence-specific binding of SRTFs to inaccessible chromatin regions, followed by LDTF recruitment and enhancer activation (bottom) (72). (C) Formation of new accessible sites rapidly occurs in vivo upon mouse cytomegalovirus or Toxoplasma gondii infection until a peak of the response is reached (69). (D) At the end of viral infection, majority of these rapidly opened chromatins return to resting state, while part of them undergo stable epigenetic poising that maintains NK cell adaptive-like or memory phenotype (69, 70).

Figure 2

A model of rapid gene induction in NK cells through higher-order chromatin architecture and remodeling. Many inducible genes in NK cells are associated with super-enhancers (SEs) that can be orderly modulated by multi-dimensional epigenetic mechanisms (72). (A) Phase separation. Phase separation occurs as a dynamic process in which transcription factors (TFs) and co-activators form non-membrane bound condensates through weak multivalent protein-protein interactions of their intrinsically disordered region (130). Multi-loop hubs bring TF-bound regulatory elements (REs) and their target genes into close proximity to finetune gene expression. (B) Super-enhancers (SEs). SEs differ from typical enhancers as they recruit large numbers of TFs and transcriptional apparatus, including co-activators, to drive high magnitude of gene induction (–132). (C) Topologically associating domains (TADs). Hi-C plots allow for visualization of three-dimensional TADs and sub-TADs, which form during the cohesin-mediated loop extrusion process. Looping can occur between two convergently oriented CCCTC-binding factor (CTCF) sites, using a cohesin ring that extrudes DNAs as shown in (A) (, –135).