Histone methyltransferase Ezh2 negatively regulates NK cell terminal maturation and function
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ABSTRACT:
PROVIDER: PRJNA733052 | ENA |
REPOSITORIES: ENA
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Project description:Deletion of Ezh2 promotes NK cell terminal differentiation and cytotoxicity with increased IFN-γ production by a potential target Pbx1.
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Project description:Our previous work indicated that the Enhancer of Zeste Homolog 2 (Ezh2) is a negative regulator of NK cell early differentiation and function by trimethylation of histone H3 lysine 27 (H3K27me3). Here, we deleted Ezh2 from immature NK and downstream progeny to explore its role in NK cell maturation by single-cell RNA sequencing (scRNA-seq). We identified six distinct NK stages based on transcriptional signature during the maturation of NK cells. Conditional deletion of Ezh2 in NK cells resulted in the maturation trajectory of NK cell arrested in CD11b SP stage 5 which is clustered with genes related to activating function of NK cells. Mechanistically, we speculated that Ezh2 plays a critical role in NK development by activating gene expression of the AP-1 superfamily independent of PRC2 function. Our results implied a novel role for the Ezh2-AP-1-Klrg1 axis to alter NK cell maturation trajectory and NK cell-mediated cytotoxicity.
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Project description:scRNA-Seq of negatively enriched NK cells 4 days post MCMV infection
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Project description:In the innate immune system, natural killer (NK) cells represent a highly important subset of cells with utmost importance in the control of transformed cell and tumour inflammation. Previous studies showed that NK cells can convert into ILC1-like cells in a TGF-β-rich tumour microenvironment (TME). In addition, cancer patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) have increased frequencies of ILC1 cells in peripheral blood mononuclear cells (PBMCs), which show reduced production of the proinflammatory cytokines IFN-γ and TNF in addition to decreased granzyme B production. Here, we identify the histone methyltransferase DOT1L as a critical regulator of NK cell lineage integrity in vitro and in vivo. NK cells from NKp46-conditional DOT1L knockout mice (DOT1L.Ncr1) show increased frequencies of ILC1-like cells (CD49b+ CD49a+), and also express more of the ILC1 markers CD200R, TRAIL, while showing reduced expression of Ly49H. We further identify that the increased ILC1-like phenotype is largely independent of TGFβ. Assessment of transcription factor (TF) availability in the absence of DOT1L shows that the Myocyte-specific enhancer factor (MEF)2C is the highest downregulated TF in the absence of DOT1L. CRISPRCas9-mediated deletion of MEF2C ultimately provides evidence that this TF is limiting NK cell plasticity in vivo. Our findings provide evidence for a previously unknown role of DOT1L and MEF2C in NK cell biology for maintaining NK cell lineage integrity and may ultimately result in improved therapies for patients with leukemia or other NK cell-lineage dependent malignancies.
2024-04-30 | GSE222234 | GEO
Project description:Epigenetic modifiers are promising targets to improve therapies in patients with cancer. Targeting the methyltransferase DOT1L with small molecule inhibitors has shown promising effects on the control of cancerous cells. However, these small molecules are given systemically and may have a profound impact on non-cancerous cells, such as the cells of the immune system. In the innate immune system, natural killer (NK) cells are a critical subset of cells with important roles in controlling transformed cells and tumour inflammation. Previous studies have shown that NK cells can convert into ILC1-like cells in a TGFβ-rich tumour microenvironment (TME). Additionally, cancer patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) have increased frequencies of ILC1 cells in peripheral blood mononuclear cells (PBMCs), which show reduced production of proinflammatory cytokines and decreased granzyme B production. In this study, we identify DOT1L as a critical regulator of NK cell activation and lineage integrity. We generated NKp46-conditional DOT1L knockout mice (DOT1L.Ncr1) and observed increased frequencies of ILC1-like cells (CD49b+ CD49a+, CD62L-) and reduced frequencies of NK cells (CD49b+ CD49a-, CD62L+) in these mice. While the absence of DOT1L increases the sensitivity to TGFβ, the increased expression of CD49a is highly intrinsic and only partially dependent on TGFβ signalling. Functionally, the increased presence of ILC1-like cells in the tumour microenvironment of DOT1L.Ncr1 mice leads to decreased tumour control. Our assessment of the transcriptional program reveals alternative uses of transcription factors, such as the AP-1 family or SMAD2/3, to maintain NK cell activation and lineage integrity. Our findings provide evidence for a previously unknown role of DOT1L in NK cell biology, and demonstrate the importance of maintaining NK cell lineage integrity for effective tumour control. These findings have significant implications for the development of improved therapies for cancer or other NK cell-lineage dependent malignancies.
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Project description:Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived memory cells following viral infection. However, the molecular mechanisms by which clonally expanded effector NK (NKeff) cells persist to form memory cells is not well understood. Utilizing single cell RNA sequencing, we identify two Ly49H+ NKeff cell populations following mouse cytomegalovirus (MCMV) infection defined by the cell surface protein Ly6C. Ly6C– NKeff cells displayed enhanced survival during the contraction phase in a BCL2-dependent manner. Ly6C– NKeff cells displayed distinct transcriptional and epigenetic signatures compared to Ly6C+ NKeff cells, with a core epigenetic signature shared with memory precursor (MP) CD8+ T cells enriched in ETS1 and Fli1 DNA-binding motifs. Fli1 regulated memory NK cell fate by promoting terminal maturation and decreased persistence of contracting NK cells. Our results suggest that memory NK cells, similar to memory T cells, are generated by a subset of epigenetically distinct MP cell states that preferentially survive during the contraction phase of the response to viral infection.
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Project description:Lytic polysaccharide monooxygenases (LPMOs) are oxidative enzymes that help break down lignocellulose, making them highly attractive for improving biomass utilization in biotechnological purposes. The catalytically essential N-terminal histidine (His1) of LPMOs is post-translationally modified by methylation in filamentous fungi to protect them from auto-oxidative inactivation, however, the responsible methyltransferase enzyme is unknown. Using mass-spectrometry-based quantitative proteomics in combination with systematic CRISPR/Cas9 knockout screening in Aspergillus nidulans, we identified the N-terminal histidine methyltransferase (NHMT) encoded by the gene AN4663. Targeted proteomics confirmed that NHMT was solely responsible for His1 methylation of LPMOs. NHMT is predicted to encode a unique seven-transmembrane segment anchoring a soluble methyltransferase domain. Co-localization studies showed endoplasmic reticulum residence of NHMT and co-expression in the industrial production yeast Komagataella phaffii with LPMOs resulted in His1 methylation of the LPMOs. This demonstrates the biotechnological potential of recombinant production of proteins and peptides harbouring this unique post-translational modification.
2023-07-14 | PXD037734 | Pride
Project description:Epigenetic modifiers are promising targets to improve therapies in patients with cancer. Targeting the methyltransferase DOT1L with small molecule inhibitors has shown promising effects on the control of cancerous cells. However, these small molecules are given systemically and may have a profound impact on non-cancerous cells, such as the cells of the immune system. In the innate immune system, natural killer (NK) cells are a critical subset of cells with important roles in controlling transformed cells and tumour inflammation. Previous studies have shown that NK cells can convert into ILC1-like cells in a TGFβ-rich tumour microenvironment (TME). Additionally, cancer patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) have increased frequencies of ILC1 cells in peripheral blood mononuclear cells (PBMCs), which show reduced production of proinflammatory cytokines and decreased granzyme B production. In this study, we identify DOT1L as a critical regulator of NK cell activation and lineage integrity. We generated NKp46-conditional DOT1L knockout mice (DOT1L.Ncr1) and observed increased frequencies of ILC1-like cells (CD49b+ CD49a+, CD62L-) and reduced frequencies of NK cells (CD49b+ CD49a-, CD62L+) in these mice. While the absence of DOT1L increases the sensitivity to TGFβ, the increased expression of CD49a is highly intrinsic and only partially dependent on TGFβ signalling. Functionally, the increased presence of ILC1-like cells in the tumour microenvironment of DOT1L.Ncr1 mice leads to decreased tumour control. Our assessment of the transcriptional program reveals alternative uses of transcription factors, such as the AP-1 family or SMAD2/3, to maintain NK cell activation and lineage integrity. Our findings provide evidence for a previously unknown role of DOT1L in NK cell biology, and demonstrate the importance of maintaining NK cell lineage integrity for effective tumour control. These findings have significant implications for the development of improved therapies for cancer or other NK cell-lineage dependent malignancies.
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