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Gene regulatory programs of NK cells show that NCAM1 (CD56) and KIRs are controlled by genetically polymorphic distal regulatory elements [scATAC-seq]

ABSTRACT: Owing to their immunoprotective properties, natural killer (NK) cells are critical for the innate response to pathogens, as well as a new wave of cancer immunotherapy that harnesses natural cytotoxicity. We sought to understand the genetic and epigenetic drivers behind human specific NK cell receptors, so that we can better understand the underlying cellular function. Here, we present a transcriptomic, proteomic (CITE-seq), and chromatin (single nuclei ATAC-seq and Hi-C) analysis of human peripheral NK cell subsets, uncovering key regulatory programs governing NK cell differentiation. Through integrative multi-omics, we demonstrate that CD56bright versus CD56dim NK cell subsets have differential distal regulatory element (DRE) landscapes, with fewer accessible DREs in the CD56dim NK cells. We combine epigenetic, chromatin looping, and human genetic data to show mechanisms governing the NCAM1 (encoding CD56) and KIR loci. For example, we identify NCAM1 DREs that bind STAT in most NK cells, while identifying a genetic cohort that has motifs for binding repressive BLIMP1 at the DRE and resulting in less CD56 expression. Together, our findings reveal novel epigenetic and transcriptomic systems for regulation of NK cells cytotoxicity and diversity, deepening our understanding of their function and how transcription factor networks govern CD56bright versus CD56dim phenotypes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297712 | GEO | 2025/05/24

REPOSITORIES: GEO

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Project description:Human Natural Killer (NK) cells comprise two main subsets, CD56bright and CD56dim cells, that differ in function, phenotype and tissue localization. To further dissect the heterogeneity of CD56dim cells, we have performed transcriptome analysis and functional ex vivo characterization of human NK cell subsets according to the expression of markers related to differentiation, migration or competence. Here, we show for the first time that the ability to respond to cytokines or to activating receptors is mutually exclusive in almost all NK cells with the exception of CD56dim CD62L+ cells. Indeed, only these cells combine the ability to produce interferon (IFN)-gamma after cytokines and proliferate in vivo during viral infection with the capacity to kill and produce cytokines upon engagement of activating receptors. Therefore, CD56dim CD62L+ cells represent a unique subset of polyfunctional NK cells. Ex vivo analysis of their function, phenotype, telomere length, frequencies during ageing as well as transfer experiments of NK cell subsets into immunodeficient mice suggest that CD56dim CD62L+ cells represent an intermediate stage of NK cell maturation, which after restimulation can accomplish multiple tasks and further develop into terminally differentiated effectors. Gene expression profiles of FACSAria sorted CD3- CD56bright CD62L+, CD3- CD56dim CD62L+ and CD3- CD56dim CD62L- NK cells from human peripheral blood of three donors were compared using Affymetrix GeneChip Human Genome HG-U133_Plus_2. After total RNA extraction, reverse transcription, cDNA extraction, the biotinylated cRNA was transcribed, fragmented, and 15 Âµg cRNA hybridized in triplicates for each of the three groups to the GeneChip arrays. Group1: CD3- CD56bright CD62L+,.Group2: CD3- CD56dim CD62L+, Group3: CD3- CD56dim CD62L-. Lists of differentially regulated genes were created using High Performance Chip Data Analysis (HPCDA) with Bioretis database (http://www.bioretis-analysis.de). Worldwide data sharing is possible via Bioretis, please ask the authors.

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Gene regulatory programs of NK cells show that NCAM1 (CD56) and KIRs are controlled by genetically polymorphic distal regulatory elements [scATAC-seq]

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