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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: CRISPR/Cas9 screens on cSAM leukemia cells

ABSTRACT: SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: CRISPR/Cas9 screens on cSAM leukemia cells

PROVIDER: PRJNA1127595 | ENA |

REPOSITORIES: ENA

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: CRISPR/Cas9 screens on cSAM leukemia cells

Project description:Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR/Cas9 library screenings using a mouse monocytic AML model, and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo was mainly dependent on NK cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulated interferon-stimulated genes and NKG2D ligands through demethylation of histone H3 Lys9 at the monocyte-specific enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects were not observed in non-monocytic leukemia cells. We also identified the expression of MNDA and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of each AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in monocytic AML and underscores its potential as a therapeutic target for current unmet needs.

2024-08-03 | GSE270630 | GEO

SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: H3K9me3 ChIP-seq of cSAM leukemia cells with Setdb1 depletion [ChIP-seq]

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: Gene expression profiles of cSAM leukemia cells with Setdb1 depletion [RNA-seq]

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: H3K9me3 ChIP-seq of cSAM leukemia cells with Setdb1 depletion [ChIP-seq]

Project description:SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: H3K9me3 ChIP-seq of cSAM leukemia cells with Setdb1 depletion [ChIP-seq]

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: Gene expression profiles of cSAM leukemia cells with Setdb1 depletion [RNA-seq]

Project description:SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: Gene expression profiles of cSAM leukemia cells with Setdb1 depletion [RNA-seq]

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Hypoxia stabilizes SETDB1 to maintain genome stability

Project description:Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins (PHD) and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element (TE)-derived double-stranded RNAs (dsRNAs), thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.

2024-01-26 | PXD037104 | Pride

Identification of Setdb1 interaction proteins in neural stem cells

Project description:Setdb1 is an epigenetic factors catalyzing modification of H3K9me3. Expression of its gene is localized to embryonic neural cells during vertebrate embryogenesis, suggesting its role in regulating neural stemness. The project is to identify the interaction partners of Setdb1, by which Setdb1 regulates neural stemness in neural stem cells.

2022-08-12 | PXD030453 | Pride

Epigenetic Silencing by SETDB1 Suppresses Tumor-cell Intrinsic Immunogenicity

Project description:Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, Dele-Oni D, Du PP, Halawi A, Ishizuka JJ, Kim S, Klaeger S, Knudsen NH, Miller BC, Nguyen T, Olander K, Papanastasiou M, Rachimi S, Robitschek EJ, Schneider EM, Yeary M, Zimmer M, Jaffe JD, Carr SA, Doench JG, Haining WN, Yates KB, Manguso RT, Bernstein BE. 2020. Epigenetic dysregulation is a defining feature of tumorigenesis and has been implicated in immune escape, yet mechanisms that drive immune evasion are poorly understood. To systematically identify epigenetic factors that modulate the immune sensitivity of tumor cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumor models treated with immune checkpoint blockade. We identified the H3K9-methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as cell-intrinsic mediators of immune escape in tumor cells. We also found that amplification of SETDB1 (1q21) in human tumors is associated with reduced cytotoxic T-cell infiltration and resistance to immune checkpoint blockade. Mechanistically, we demonstrate that SETDB1 represses broad domains, hundreds of kilobases in size, many of which reside within the open genome compartment. These SETDB1 domains are enriched for transposable elements (TEs) and immune gene clusters associated with segmental duplication events, a central mechanism of mammalian genome evolution. SETDB1 loss derepresses latent TE-encoded regulatory elements and proximal immune genes within these repetitive regions, including canonical co-stimulatory ligands, and induces hundreds of putative TE-encoded viral antigens. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses intrinsic immunogenicity in cancer cells, and thus represents a candidate target for immunotherapy.

2020-12-11 | MSV000086580 | MassIVE

Epigenetic Silencing by SETDB1 Suppresses Tumor-cell Intrinsic Immunogenicity

Project description:Epigenetic dysregulation is a defining feature of tumorigenesis and has been implicated in immune escape. However, the epigenetic mechanisms that drive immune evasion in cancer are poorly understood. To systematically identify epigenetic factors that modulate the immune sensitivity of tumor cells, we performed in vivo loss of function screens targeting 936 chromatin regulators in mouse tumor models treated with immune checkpoint blockade. We identified the H3K9-methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as cell-intrinsic mediators of immune escape in tumor cells. We also found that amplification of SETDB1 (1q21) in human tumors is associated with reduced cytotoxic T-cell infiltration and resistance to immune checkpoint blockade. Mechanistically, we demonstrate that SETDB1 targets broad domains, hundreds of kilobases in size, many of which reside within the open genome compartment. These SETDB1 domains are enriched for transposable elements (TEs) and immune gene clusters associated with segmental duplication events, a central mechanism of mammalian genome evolution. SETDB1 loss derepresses latent TE-encoded regulatory elements and proximal immune genes within these repetitive regions, including canonical NKG2D ligands, and induces hundreds of putative TE-encoded viral antigens. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses intrinsic immunogenicity in cancer cells, and thus represents a candidate target for immunotherapy.

2021-03-18 | GSE155972 | GEO

DMD-TGFb-SETDB1

Project description:DMD-TGFb-SETDB1

| PRJEB63300 | ENA