Lineage-specific transition of histone signatures in the killer cell Ig-like receptor locus from hematopoietic progenitor to NK cells (original) (raw)
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DNA Methylation Maintains Allele-specific KIR Gene Expression in Human Natural Killer Cells
Journal of Experimental Medicine, 2003
Killer immunoglobulin-like receptors (KIR) bind self–major histocompatibility complex class I molecules, allowing natural killer (NK) cells to recognize aberrant cells that have down-regulated class I. NK cells express variable numbers and combinations of highly homologous clonally restricted KIR genes, but uniformly express KIR2DL4. We show that NK clones express both 2DL4 alleles and either one or both alleles of the clonally restricted KIR 3DL1 and 3DL2 genes. Despite allele-independent expression, 3DL1 alleles differed in the core promoter by only one or two nucleotides. Allele-specific 3DL1 gene expression correlated with promoter and 5′ gene DNA hypomethylation in NK cells in vitro and in vivo. The DNA methylase inhibitor, 5-aza-2′-deoxycytidine, induced KIR DNA hypomethylation and heterogeneous expression of multiple KIR genes. Thus, NK cells use DNA methylation to maintain clonally restricted expression of highly homologous KIR genes and alleles.
European Journal of Immunology, 2007
NK cells detect altered patterns of HLA expression in infections and tumors using a variegated repertoire of killer cell Ig-like receptors (KIR). Each clone surveys different HLA molecules by expressing a limited subset of the KIR encoded in its genome, which is maintained throughout cell divisions by epigenetic mechanisms (methylation of the nonexpressed genes). How KIR repertoires are acquired remains, however, unexplained. Human KIR2DL5 is a useful model for studying KIR expression because it has alleles with similar coding regions, but drastically divergent expression-whilst some are transcribed in a typically clonal manner, others, with distinctive promoter polymorphisms, are nonexpressed. Here we investigate the relationship between the sequence diversity of KIR2DL5, including three novel alleles, and its variable transcription. The promoters of the transcribed alleles recruit the transcriptional regulator RUNX3, whilst a mutation shared by all silent alleles precludes this binding. However, all promoters are functional in vitro, and pharmacological DNA demethylation of NK cells rescues the transcription of silent alleles, indicating that only epigenetic mechanisms prevent their inclusion in a normal KIR repertoire. Our results are consistent with a model in which RUNX factors could function as switch elements in the acquisition of KIR repertoires by NK cell precursors.
The Journal of experimental medicine, 2015
The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin-based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4(+) cells that express a non-iNKT cell specific T cell repertoire. In ...
BMC Cell Biology, 2014
Background: Epigenetic regulation is known to affect gene expression, and recent research shows that aberrant DNA methylation patterning and histone modifications may play a role in leukemogenesis. In order to highlight the cooperation of epigenetic mechanisms acting during the latter process it is important to clarify their potential as biomarkers of granulocytic differentiation. Results: In this study we investigated epigenetic alterations in human hematopoietic cells at a distinct differentiation stages: primary hematopoietic CD34+ cells, KG1 myeloid leukemic cells, whose development is stopped at early stage of differentiation, and mature neutrophils. We focused on the epigenetic status of cell cycle regulating (p15, p16) and differentiation related (E-cadherin and RARβ) genes. We found that the methylation level in promoter regions of some of these genes was considerably higher in KG1 cells and lower in CD34+ cells and human neutrophils. As examined and evaluated by computer-assisted methods, histone H3 and H4 modifications, i.e. H3K4Me3, H3K9Ac, H3K9Ac/S10Ph and H4 hyperAc, were similar in CD34+ cells and human mature neutrophils. By contrast, in the KG1 cells, histone H3 and H4 modifications were quite high and increased after induction of granulocytic differentiation with the HDAC inhibitor phenyl butyrate. Conclusions: We found the methylation status of the examined gene promoters and histone modifications to be characteristically associated with the hematopoietic cell progenitor state, induced to differentiate myeloid KG1 cells and normal blood neutrophils. This could be achieved through epigenetic regulation of E-cadherin, p15, p16 and RARβ genes expression caused by DNA methylation/demethylation, core and linker histones distribution in stem hematopoietic cells, induced to differentiation KG1 cells and mature human neutrophils, as well as the histone modifications H3K4Me3, H3K9Ac, H3K9Ac/S10Ph and H4 hyperAc in relation to hematopoietic cell differentiation to granulocyte. These findings also suggest them as potentially important biomarkers of hematopoietic cell granulocytic differentiation and could be valuable for leukemia induced differentiation therapy.
Frontiers in oncology, 2013
Epigenetic drugs like histone deacetylase inhibitors (HDACi) and DNA-methyltransferase inhibitors (DNMTi) have been shown to be effective against a variety of tumor entities. Among different molecular anticancer activities of epigenetic active substances, up-regulation of natural killer (NK) cell ligands was described to contribute to an enhanced NK cell-mediated killing of tumor cell lines. So far, no data is available on this effect in childhood acute lymphoblastic leukemia. We investigated the effect of two HDACi [vorinostat, valproic acid (VPA)] and two DNMTi (azacytidine, decitabine) on the viability, expression of NK ligands, and NK susceptibility of the pre-B-cell-ALL cell line MHH-CALL-4. Whereas vorinostat, azacytidine, and decitabine directly reduced viability of the cell line, VPA had no direct cytotoxic effect. NKG2D-ligands were expressed only at very low levels and not affected by epigenetic treatment. Higher expression was found for the DNAM-1 ligands with significant...
Epigenetic analysis of human γδ T lymphocytes
2017
Human γδ T-cells have emerged as key players in diverse immune responses both in health and disease. Such a dynamic functional diversity of cells is controlled at various levels of epi)genetic regulation in an orchestrated manner. However, a comprehensive overview of epigenetic mechanisms dictating human γδ T-cell development, regulation and molecular function is largely missing. The present thesis aims at elucidating the epigenetic landscape of human γδ T-cells by mainly two distinct approaches. In a first approach based on in vitro culture, the NKG2D ligand expression and release, and its further implications on NKG2D receptor expression by epigenetic inhibitors such as histone deacetylase inhibitor valproic acid, a drug widely used in the clinic, was studied. The modulation of NKG2D receptor expression and function of γδ T cells in co-culture with pancreatic carcinoma and prostate carcinoma tumor cell lines were addressed. Additionally, the effect on functional responses of γδ T-...
The Journal of biological chemistry, 2018
Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically, but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic Jumonji domain-containing protein 3 (JMJD3/UTX) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-γ, TNFα, granulocyte-macrophage ...
Epigenetics of haematopoietic cell development
Nature Reviews Immunology, 2011
Mechanisms that confer heritable, but potentially reversible, states of gene activity that are imposed by the structure of chromatin or covalent modifications of DNA and histones.