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Targeting Setdb1 in T Cells Induces Transplant Tolerance without Compromising Antitumor Immunity

ABSTRACT: Targeting Setdb1 in T Cells Induces Transplant Tolerance without Compromising Antitumor Immunity

PROVIDER: PRJNA1216646 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32156700_1.fastq.gz	Fastqsanger.gz
	SRR32156700_2.fastq.gz	Fastqsanger.gz
	SRR32156701_1.fastq.gz	Fastqsanger.gz
	SRR32156701_2.fastq.gz	Fastqsanger.gz
	SRR32156702_1.fastq.gz	Fastqsanger.gz

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Targeting Setdb1 in T Cells Induces Transplant Tolerance without Compromising Antitumor Immunity

Project description:Suppressing immune responses promotes allograft survival but also favors tumor progression and recurrence. How to selectively suppress allograft rejection while maintaining or even enhancing antitumor immunity is challenging. Here, we found mice deficient in Setdb1, an H3K9 methyltransferase, retained allograft-related rejection but exhibited retentive antitumor immunity. RNA-Seq showed that Setdb1 deficiency did not affect T-cell activation or cytokine production, but it induced an increase in regulatory T (Treg) cell-associated gene expression. Treg cell depletion impaired graft acceptance in Setdb1-deficient mice, indicating that the Treg cells promoted allograft survival. Surprisingly, Treg cell-specific Setdb1 deficiency did not prolong allograft survival, suggesting that Setdb1 may function prior to Foxp3 induction. Using single-cell RNA sequencing, we found that Setdb1 deficiency induced a new Treg population in the thymus. This subset of Treg cells expressed less IL-1R2 and IL-18R1. Mechanistically, during Treg cell induction, Setdb1 was recruited by transcription factor ATF and modified histone methylation. Our data define Setdb1 in T cells as a target for suppressing allograft rejection while maintaining antitumor immunity.

2025-03-17 | GSE288264 | GEO

SETDB1-TRIM28 complex suppresses antitumor immunity [RNA-seq]

Project description:Epigenetic mechanism contributes to immune landscapes in cancer. Here we identify the SETDB1-TRIM28 complex as a critical suppressor of antitumor immunity. An epigenetic CRISPR-Cas9 screen of 1,218 chromatin regulators identified TRIM28 as a novel suppressor of PD-L1 expression. We revealed that expression of the SETDB1-TRIM28 complex negatively correlates with infiltration of effector CD8+ T cells. Inhibition of SETDB1-TRIM28 simultaneously upregulates PD-L1 and activates the cGAS-STING innate immune response to increase infiltration of CD8+ T cells. Mechanistically, SETDB1-TRIM28 inhibition leads to micronuclei formation in cytoplasm, a known activator of the cGAS-STING pathway. Thus, SETDB1-TRIM28 inhibition bridges the innate and adaptive immunity. Indeed, SETDB1 knockout enhances the antitumor effects of immune checkpoint blockade anti-PD-L1 in an ovarian cancer mouse model in a cGAS dependent manner. Our findings establish SETDB1-TRIM28 complex as a regulator of antitumor immunity and its loss activates cGAS-STING innate immunity to boost antitumor effects of immune checkpoint blockades.

2021-10-20 | GSE182089 | GEO

SETDB1-TRIM28 complex suppresses antitumor immunity [CRISPR/Cas9 screen]

2021-10-20 | GSE182197 | GEO

SETDB1-TRIM28 complex suppresses antitumor immunity

Project description:SETDB1-TRIM28 complex suppresses antitumor immunity

| PRJNA755287 | ENA

SETDB1-TRIM28 complex suppresses antitumor immunity [RNA-seq]

Project description:SETDB1-TRIM28 complex suppresses antitumor immunity [RNA-seq]

| PRJNA754434 | ENA

SETDB1-TRIM28 complex suppresses antitumor immunity [CRISPR/Cas9 screen]

Project description:SETDB1-TRIM28 complex suppresses antitumor immunity [CRISPR/Cas9 screen]

| PRJNA755293 | ENA

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

Systemic application of honokiol prevents cisplatin ototoxicity without compromising its antitumor effect.

Project description:Cisplatin is a potent drug used in about 40% of cancer treatment but also leads to severe deafness in 60-80% of the cases. Although the mechanism is known to be related to the accumulation of reactive oxygen species (ROS), no drug or FDA approved treatment is currently available to prevent cisplatin ototoxicity. With this study, we show for the first time that honokiol (HNK), a pleiotropic poly-phenol prevents cisplatin-induced hearing loss. HNK also improves the wellbeing of the mice during the treatment, determined by the increase in the number of surviving animals. In a transgenic tumor mouse model, HNK does not hinder cisplatin's antitumor effect. The mechanism is related to the activation of sirtuin 3, a deacetylase in mitochondria essential for ROS detoxification. We expect a paradigm shift in cisplatin chemotherapy based on the current study and future clinical trials, where honokiol is applied to reduce side effects including hearing loss.

| S-EPMC7783741 | biostudies-literature

DMD-TGFb-SETDB1

Project description:DMD-TGFb-SETDB1

| PRJEB63300 | ENA