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ATF7IP-mediated stabilization of the histone methyltransferase SETDB1 is essential for heterochromatin formation by the HUSH complex

ABSTRACT: ATF7IP-mediated stabilization of the histone methyltransferase SETDB1 is essential for heterochromatin formation by the HUSH complex

PROVIDER: PRJNA342607 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4237730_1.fastq.gz	Fastqsanger.gz
	SRR4237730_2.fastq.gz	Fastqsanger.gz
	SRR4237731_1.fastq.gz	Fastqsanger.gz
	SRR4237731_2.fastq.gz	Fastqsanger.gz
	SRR4237722.fastq.gz	Fastqsanger.gz

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Similar Datasets

ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex.

Project description:The histone methyltransferase SETDB1 plays a central role in repressive chromatin processes, but the functional requirement for its binding partner ATF7IP has remained enigmatic. Here, we show that ATF7IP is essential for SETDB1 stability: nuclear SETDB1 protein is degraded by the proteasome upon ablation of ATF7IP. As a result, ATF7IP is critical for repression that requires H3K9 trimethylation by SETDB1, including transgene silencing by the HUSH complex. Furthermore, we show that loss of ATF7IP phenocopies loss of SETDB1 in genome-wide assays. ATF7IP and SETDB1 knockout cells exhibit near-identical defects in the global deposition of H3K9me3, which results in similar dysregulation of the transcriptome. Overall, these data identify a critical functional role for ATF7IP in heterochromatin formation by regulating SETDB1 abundance in the nucleus.

| S-EPMC5081395 | biostudies-literature

Assessing the impact of loss of ATF7IP and SETDB1 on the transcriptome

Project description:By comparing HeLa cells lacking ATF7IP or SETDB1 generated through CRISPR/Cas9-mediated gene disruption to wild-type HeLa cells, the goal of the experiment was to determine the effect of loss of the SETDB1•ATF7IP complex on the transcriptome.

2016-10-11 | GSE86813 | GEO

Assessing the impact of loss of ATF7IP and SETDB1 on the global distribution of H3K9me3

2016-10-11 | GSE86811 | GEO

Targeting the Atf7ip-Setdb1 complex augments anti-tumor immunity by boosting tumor immunogenicity

Project description:Despite substantial progress that has been made in understanding how tumors escape immune surveillance, measures to counteract tumor immune evasion have been limited. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify novel epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen targeting genes encoding epigenetic modifiers. We found that genetic disruption of the chromatin modifiers Atf7ip or its interacting partner Setdb1 in tumor cells restored tumor antigen expression, resulting in augmented tumor immunogenicity concomitant with elevated endogenous retroviral antigens (ERVs), mRNA intron retention. ERVs disinhibition was associated with a robust type I interferon response and increased T cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.

2021-07-23 | GSE179574 | GEO

ATF7IP-mediated stabilization of the histone methyltransferase SETDB1 is essential for heterochromatin formation by the HUSH complex

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-10-11 | GSE86814 | GEO

The HUSH-SETDB1-MORC2 epigenetic repressor complex restricts herpesvirus infection in association with PML nuclear bodies

Project description:The establishment of latent herpes simplex virus 1 (HSV-1) infection is controlled by promyelocytic leukemia nuclear bodies (PML NBs). Viral genomes are recruited to PML NBs structures and chromatinized by repressive H3.3K9me3 modified H3.3 histone variant to form viral DNA-containing PML-NBs (vDCP NBs). Exactly how this occurs is unclear. Here we identify an essential role for the HUSH complex and its SETDB1 and MORC2 effectors in the establishment and maintenance of latent herpes simplex virus 1 (HSV-1) infection. ChIP-seq analyses conducted on latently/quiescently infected primary human fibroblasts highlight the association of the H3K9me3 mark with the entire viral genome. We demonstrate the necessity of HUSH, SETDB1, and MORC2 in the establishment of repressive heterochromatin in vDCP NBs. Depletion of these components prior to viral infection results in reduced H3K9me3 levels across the entirety of latent/quiescent HSV-1 genomes, with minimal impact on the cellular genome as a whole. Once latency is established, depletion of HUSH, SETDB1, or MORC2 by shRNAs or the HIV-2ROD Vpx protein, induces the reactivation of HSV-1 in infected primary human fibroblasts as well as in human induced pluripotent stem cell-derived sensory neurons (hiPSDN). We discovered that the viral protein ICP0 induces MORC2 degradation via the proteasome machinery. This process is concurrent with ICP0 capability to initiate full HSV-1 reactivation, as well as the significant reactivation of HSV-1 upon MORC2 depletion in hiPSDN. Our data demonstrate the potent antiviral restriction activity of the HUSH/SETDB1/MORC2 complex to a non-integrated human herpesvirus, its close association with PML NBs, and introduces a new target for anti-herpesvirus therapy.

2024-09-24 | GSE263436 | GEO

MGA directly recruits SETDB1/ATF7IP for histone H3K9me3 on meiosis-related genes in mouse embryonic stem cells.

Project description:Many of meiosis-related genes in mouse embryonic stem cells (ESCs) bear substantial amounts of trimethylated lysine 9 of histone H3 (H3K9me3) modification. However, how meiosis-related genes in ESCs acquire this histone modification is totally obscure. We hypothesize that the specific functional domain termed FAM of MGA that is the scaffolding component of PRC1.6, one of atypical subtypes of PRC1 is directly involved in the deposition of this histone modification by recruiting SETDB1 via its interaction with ATF7IP. To address the hypothesis, we generated ESCs producing MGA that lacks FAM domain and examined effects of the mutation on global expression profile and H3K9me3 levels by RNA- and ChIP-sequence analyses, respectively. We also generated ESCs producing mutant ATF7IP lacking its FNIII domain that is considered to be crucial for the interaction with MGA in our hypothesis to assess the role of the domain for the deposition of H3K9me3 by ChIP-seq analyses.

2025-06-19 | GSE268907 | GEO

Targeting the Atf7ip-Setdb1 complex augments anti-tumor immunity by boosting tumor immunogenicity

Project description:Targeting the Atf7ip-Setdb1 complex augments anti-tumor immunity by boosting tumor immunogenicity

| PRJNA744222 | ENA

ATF7IP inhibits Sorafenib-induced ferroptosis in hepatocellular carcinoma cells by inhibiting CYB5R2 transcription and stabilizing PARK7 protein

Project description:Ferroptosis, an iron-dependent form of programmed cell death, arises from the accumulation of lipid peroxides at toxic levels. Sorafenib, a first-line treatment for advanced hepatocellular carcinoma (HCC), shows limited clinical efficacy due to drug resistance. However, the mechanisms underlying Sorafenib resistance, especially related to ferroptosis, remain poorly understood. In this study, we extend our previous research by identifying activating transcription factor 7-interacting protein (ATF7IP) as a key inhibitor of ferroptosis. ATF7IP depletion promotes Sorafenib-induced ferroptosis, resulting in decreased cell viability, reduced cellular glutathione level, increased lipid peroxidation, and altered mitochondrial crista structure. Notably, ATF7IP knockdown showed cooperative effects with Sorafenib in inhibiting HCC growth in mice. Mechanistically, ATF7IP interacts with SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to epigenetically silence the transcription of cytochrome b5 reductase 2 (CYB5R2), thereby reducing cellular Fe2+ levels. Meanwhile, ATF7IP inhibits Sorafenib-induced ferroptosis also by stabilizing the antioxidant sensor Parkinsonism-associated deglycase (PARK7) protein which preserves the transsulfuration pathway to produce glutathione (GSH). In conclusion, our findings identify ATF7IP as a critical ferroptosis inhibitor and represent ATF7IP as a novel therapeutic target for Sorafenib-based combination therapies of HCC.

2025-04-14 | GSE294091 | GEO

Methyltransferase Setdb1 Promotes Osteoblast Proliferation by Epigenetically Silencing Macrod2 with the Assistance of Atf7ip.

Project description:Bone loss caused by mechanical unloading is a threat to prolonged space flight and human health. Epigenetic modifications play a crucial role in varied biological processes, but the mechanism of histone modification on unloading-induced bone loss has rarely been studied. Here, we discovered for the first time that the methyltransferase Setdb1 was downregulated under the mechanical unloading both in vitro and in vivo so as to attenuate osteoblast proliferation. Furthermore, we found these interesting processes depended on the repression of Macrod2 expression triggered by Setdb1 catalyzing the formation of H3K9me3 in the promoter region. Mechanically, we revealed that Macrod2 was upregulated under mechanical unloading and suppressed osteoblast proliferation through the GSK-3β/β-catenin signaling pathway. Moreover, Atf7ip cooperatively contributed to osteoblast proliferation by changing the localization of Setdb1 under mechanical loading. In summary, this research elucidated the role of the Atf7ip/Setdb1/Macrod2 axis in osteoblast proliferation under mechanical unloading for the first time, which can be a potential protective strategy against unloading-induced bone loss.

| S-EPMC9406310 | biostudies-literature

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