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.

Transcriptional enhancers and their communication with gene promoters

“…We have left the discussions on the dynamics of enhancer–promoter looping in specific biological settings outside the scope of this review. Several recent articles have provided up-to-date perspectives in this regard for various systems, including lymphocyte development [ 250 , 251 ], heart development and disease [ 252 ], and cancer [ 253 ].…”

Transcription factor TFII-I fine tunes innate properties of B lymphocytes

“…Although TFII-I is a transcription factor that functions via cis-regulatory elements and expected to impact chromatin accessibility, this has not been directly explored. Open chromatin impressions are associated with cellular identities ( 36 ), thus to address whether absence of TFII-I would alter chromatin landscape of FO and MZ B cells, we performed Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) ( 37 ), using sorted FO and MZ B cells from WT and cKO spleens. After quality checks and alignment to the mouse genome, open chromatin regions (peaks) were called using MACS2 algorithm.…”

NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis

“…CD56 dim NK cells represent around 90% of total PB NK cells and are characterized by the high expression of CD16 and a higher potential to kill tumor cells, while CD56 bright NK cells express higher levels of CD94-NKG2A heterodimers and primarily produce large amounts of cytokines including IFN-γ and tumor necrosis factor (TNF)-α [ 51 , 52 ]. These NK cell subsets also differ for the expression of chemokine receptors and homing properties as well as for transcriptomic and epigenetic regulatory programs [ 47 , 53 , 54 , 55 , 56 , 57 ]. In mice, three main NK cell subsets have been identified according to the expression of CD27, a member of the TNF receptor superfamily, and the integrin chain CD11b; these cells also differ for functions and homing receptors [ 58 , 59 , 60 , 61 ].…”