Gene regulatory programs of NK cells show that NCAM1 (CD56) and KIRs are controlled by genetically polymorphic distal regulatory elements
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE298200 | GEO | 2025/05/28
REPOSITORIES: GEO
Similar Datasets
Project description: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.
2025-05-24 | GSE297712 | GEO
Project description: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.
2025-05-27 | GSE298188 | GEO
Project description:Gene regulatory programs of NK cells show that NCAM1 (CD56) and KIRs are controlled by genetically polymorphic distal regulatory elements
| PRJNA1268504 | ENA
Project description:Gene regulatory programs of NK cells show that NCAM1 (CD56) and KIRs are controlled by genetically polymorphic distal regulatory elements [CITE-seq]
| PRJNA1268494 | ENA
Project description:Gene regulatory programs of NK cells show that NCAM1 (CD56) and KIRs are controlled by genetically polymorphic distal regulatory elements [scATAC-seq]
| PRJNA1265757 | ENA
Project description:Previous studies have identified multiple conserved noncoding sequences (CNS) at the mouse Ifng locus sufficient for enhancer activity in cell-based assays. These studies do not directly address biology of the human IFNG locus in a genomic setting. IFNG enhancers may be functionally redundant or each may be functionally unique. We test the hypothesis that each IFNG enhancer has a unique necessary function using a bacterial artificial chromosome transgenic model. We find that CNS-30, CNS-4, and CNS+20 are required at distinct stages of Th1 differentiation, whereas CNS-16 has a repressive role in Th1 and Th2 cells. CNS+20 is required for IFN-? expression by memory Th1 cells and NKT cells. CNS-4 is required for IFN-? expression by effector Th1 cells. In contrast, CNS-16, CNS-4, and CNS+20 are each partially required for human IFN-? expression by NK cells. Thus, IFNG CNS enhancers have redundant necessary functions in NK cells but unique necessary functions in Th cells. These results also demonstrate that distinct CNSs are required to transcribe IFNG at each stage of the Th1 differentiation pathway.
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Project description:BackgroundThe data deluge can leverage sophisticated ML techniques for functionally annotating the regulatory non-coding genome. The challenge lies in selecting the appropriate classifier for the specific functional annotation problem, within the bounds of the hardware constraints and the model's complexity. In our system AIKYATAN, we annotate distal epigenomic regulatory sites, e.g., enhancers. Specifically, we develop a binary classifier that classifies genome sequences as distal regulatory regions or not, given their histone modifications' combinatorial signatures. This problem is challenging because the regulatory regions are distal to the genes, with diverse signatures across classes (e.g., enhancers and insulators) and even within each class (e.g., different enhancer sub-classes).ResultsWe develop a suite of ML models, under the banner AIKYATAN, including SVM models, random forest variants, and deep learning architectures, for distal regulatory element (DRE) detection. We demonstrate, with strong empirical evidence, deep learning approaches have a computational advantage. Plus, convolutional neural networks (CNN) provide the best-in-class accuracy, superior to the vanilla variant. With the human embryonic cell line H1, CNN achieves an accuracy of 97.9% and an order of magnitude lower runtime than the kernel SVM. Running on a GPU, the training time is sped up 21x and 30x (over CPU) for DNN and CNN, respectively. Finally, our CNN model enjoys superior prediction performance vis-'a-vis the competition. Specifically, AIKYATAN-CNN achieved 40% higher validation rate versus CSIANN and the same accuracy as RFECS.ConclusionsOur exhaustive experiments using an array of ML tools validate the need for a model that is not only expressive but can scale with increasing data volumes and diversity. In addition, a subset of these datasets have image-like properties and benefit from spatial pooling of features. Our AIKYATAN suite leverages diverse epigenomic datasets that can then be modeled using CNNs with optimized activation and pooling functions. The goal is to capture the salient features of the integrated epigenomic datasets for deciphering the distal (non-coding) regulatory elements, which have been found to be associated with functional variants. Our source code will be made publicly available at: https://bitbucket.org/cellsandmachines/aikyatan.
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Project description:Gene regulation in mammals involves a complex interplay between promoters and distal regulatory elements that function in concert to drive precise spatiotemporal gene expression programs. However, the dynamics of the distal gene regulatory landscape and its function in the transcriptional reprogramming that underlies neurogenesis and neuronal activity remain largely unknown. Here, we performed a combinatorial analysis of genome-wide data sets for chromatin accessibility (FAIRE-seq) and the enhancer mark H3K27ac, revealing the highly dynamic nature of distal gene regulation during neurogenesis, which gets progressively restricted to distinct genomic regions as neurons acquire a post-mitotic, terminally differentiated state. We further find that the distal accessible and active regions serve as target sites for distinct transcription factors that function in a stage-specific manner to contribute to the transcriptional program underlying neuronal commitment and maturation. Mature neurons respond to a sustained activity of NMDA receptors by epigenetic reprogramming at a large number of distal regulatory regions as well as dramatic reorganization of super-enhancers. Such massive remodeling of the distal regulatory landscape in turn results in a transcriptome that confers a transient loss of neuronal identity and gain of cellular plasticity. Furthermore, NMDA receptor activity also induces many novel prosurvival genes that function in neuroprotective pathways. Taken together, these findings reveal the dynamics of the distal regulatory landscape during neurogenesis and uncover novel regulatory elements that function in concert with epigenetic mechanisms and transcription factors to generate the transcriptome underlying neuronal development and activity.
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Project description:The precise splicing of genes confers an enormous transcriptional complexity to the human genome. The majority of gene splicing occurs cotranscriptionally, permitting epigenetic modifications to affect splicing outcomes. Here we show that select exonic regions are demarcated within the three-dimensional structure of the human genome. We identify a subset of exons that exhibit DNase I hypersensitivity and are accompanied by 'phantom' signals in chromatin immunoprecipitation and sequencing (ChIP-seq) that result from cross-linking with proximal promoter- or enhancer-bound factors. The capture of structural features by ChIP-seq is confirmed by chromatin interaction analysis that resolves local intragenic loops that fold exons close to cognate promoters while excluding intervening intronic sequences. These interactions of exons with promoters and enhancers are enriched for alternative splicing events, an effect reflected in cell type-specific periexonic DNase I hypersensitivity patterns. Collectively, our results connect local genome topography, chromatin structure and cis-regulatory landscapes with the generation of human transcriptional complexity by cotranscriptional splicing.
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Project description:Human natural killer (NK) cells are defined as CD56+CD3-. Despite its ubiquitous expression on human NK cells the role of CD56 (NCAM) in human NK cell cytotoxic function has not been defined. In non-immune cells, NCAM can induce signaling, mediate adhesion, and promote exocytosis through interactions with focal adhesion kinase (FAK). Here we demonstrate that deletion of CD56 on the NK92 cell line leads to impaired cytotoxic function. CD56-knockout (KO) cells fail to polarize during immunological synapse (IS) formation and have severely impaired exocytosis of lytic granules. Phosphorylation of the FAK family member Pyk2 at tyrosine 402 is decreased in NK92 CD56-KO cells, demonstrating a functional link between CD56 and signaling in human NK cells. Cytotoxicity, lytic granule exocytosis, and the phosphorylation of Pyk2 are rescued by the reintroduction of CD56. These data highlight a novel functional role for CD56 in stimulating exocytosis and promoting cytotoxicity in human NK cells.
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