Essential roles of Windei and nuclear monoubiquitination of Eggless/SETDB1 in transposon silencing
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ABSTRACT:
PROVIDER: PRJNA526876 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8721834.fastq.gz | Fastqsanger.gz | |||
| SRR8721835.fastq.gz | Fastqsanger.gz | |||
| SRR8721836.fastq.gz | Fastqsanger.gz | |||
| SRR8721837.fastq.gz | Fastqsanger.gz | |||
| SRR9659710.fastq.gz | Fastqsanger.gz |
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Project description:Eggless/SETDB1 (Egg), the only essential histone methyltransferase (HMT) in Drosophila, plays a role in gene repression, including piRNA‐mediated transposon silencing in the ovaries. Previous studies suggested that Egg is post‐translationally modified and showed that Windei (Wde) regulates Egg nuclear localization through protein–protein interaction. Monoubiquitination of mammalian SETDB1 is necessary for the HMT activity. Here, using cultured ovarian somatic cells, we show that Egg is monoubiquitinated and phosphorylated but that only monoubiquitination is required for piRNA‐mediated transposon repression. Egg monoubiquitination occurs in the nucleus. Egg has its own nuclear localization signal, and the nuclear import of Egg is Wde‐independent. Wde recruits Egg to the chromatin at target gene silencing loci, but their interaction is monoubiquitin‐independent. The abundance of nuclear Egg is governed by that of nuclear Wde. These results illuminate essential roles of nuclear monoubiquitination of Egg and the role of Wde in piRNA‐mediated transposon repression.
2019-10-03 | GSE128203 | GEO
Project description:Eggless/SETDB1 (Egg), the only essential histone methyltransferase (HMT) in Drosophila, plays a role in gene repression, including piRNA-mediated transposon silencing in the ovaries. Previous studies suggested that Egg is post-translationally modified and showed that Windei (Wde) regulates Egg nuclear localization through protein-protein interaction. Monoubiquitination of mammalian SETDB1 is necessary for the HMT activity. Here, using cultured ovarian somatic cells, we show that Egg is monoubiquitinated and phosphorylated but that only monoubiquitination is required for piRNA-mediated transposon repression. Egg monoubiquitination occurs in the nucleus. Egg has its own nuclear localization signal, and the nuclear import of Egg is Wde-independent. Wde recruits Egg to the chromatin at target gene silencing loci, but their interaction is monoubiquitin-independent. The abundance of nuclear Egg is governed by that of nuclear Wde. These results illuminate essential roles of nuclear monoubiquitination of Egg and the role of Wde in piRNA-mediated transposon repression.
| S-EPMC6893296 | biostudies-literature
Project description:Eggless/SETDB1 (Egg), the only essential histone methyltransferase (HMT) in Drosophila, plays a role in gene repression, including piRNA-mediated transposon silencing in the ovaries. Previous studies suggested that Egg is post-translationally modified and showed that Windei (Wde) regulates Egg nuclear localization through protein-protein interaction. Monoubiquitination of mammalian SETDB1 is necessary for the HMT activity. Here, using cultured ovarian somatic cells, we show that Egg is monoubiquitinated and phosphorylated but that only monoubiquitination is required for piRNA-mediated transposon repression. Egg monoubiquitination occurs in the nucleus. Egg has its own nuclear localization signal and the nuclear import of Egg is Wde-independent. Wde recruits Egg to the chromatin at target gene silencing loci but their interaction is monoubiquitin-independent. The abundance of nuclear Egg is governed by that of nuclear Wde. These results illuminate essential roles of nuclear monoubiquitination of Egg and the role of Wde in piRNA-mediated transposon repression.
| S-SCDT-EMBOR-2019-48296V1 | biostudies-other
Project description:Investigation of expression differences between melanomas harvested from MiniCoopR-GFP versus MiniCoopR-SETDB1 transgenic zebrafish. An eight-chip study using total RNA prepared from four distinct melanomas from zebrafish injected with MiniCoopR-GFP (control) transposon and four distinct melanomas from zebrafish injected with MiniCoopR-SETDB1 transposon. Injected animals carried a p53 loss-of-function mutation, a mutation in nacre, and an mitf:BRAF-V600E transgene. Each chip measures the expression level of 32,292 genes.
2011-01-07 | E-GEOD-21505 | biostudies-arrayexpress
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
Project description:Oocytes develop the competence for meiosis and early embryogenesis during their growth. Setdb1 is a histone H3 lysine 9 (H3K9) methyltransferase required for post-implantation development and has been implicated in the transcriptional silencing of genes and endogenous retroviral elements (ERVs). To address its role in oogenesis and pre-implantation development, we conditionally deleted Setdb1 in growing oocytes. Loss of Setdb1 expression greatly impaired meiosis. It delayed meiotic resumption, altered the dynamics of chromatin condensation, and impaired kinetochore-spindle interactions, bipolar spindle organization, and chromosome segregation in more mature oocytes. The observed phenotypes related to changes in abundance of specific transcripts in mutant oocytes. Setdb1 maternally deficient embryos arrested during pre-implantation development and showed comparable defects during cell cycle progression and in chromosome segregation. Finally, transcriptional profiling data indicate that Setdb1 down-regulates rather than silences expression of ERVK and ERVL-MaLR retrotransposons and associated chimearic transcripts during oogenesis. Our results identify Setdb1 as a novel meiotic and embryonic competence factor in meiosis and mitosis, safeguarding genome integrity at the onset of life. We performed expression profiling on pools of 16 denuded GV-oocytes isolated per mouse. We used oocytes from 4 Setdb1 f/+; Zp3-cre mice and 2 Setdb1 f/- mice as controls and oocytes from 4 Setdb1 f/-; Zp3-cre mice as mutant.
2016-06-27 | E-GEOD-82002 | biostudies-arrayexpress
Project description:Copy number gain/amplification of SETDB1 has been found in several human cancers, but the detailed oncogenic mechanism(s) of SETDB1 contributing to breast cancer remains largely unexplored. In this project, we analyzed the transcriptome of human breast cancer cell lines (MDA-MB-231 and MDA-MB-453) upon silencing of SETDB1 to explore the potential mechanism(s) underlying SETDB1 promoted breast cancer. In MDA-MB-231 cells, SETDB1 was silenced by shRNA-1. In MDA-MB-453 cells, SETDB1 was reduced by shRNA-3.
2018-05-01 | GSE108656 | GEO
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
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
Project description:Meiotic synapsis and recombination ensure correct homologous segregation and genetic diversity. Asynapsed homologues are transcriptionally inactivated by meiotic silencing, which serves a surveillance function and in males drives meiotic sex chromosome inactivation. Silencing depends on the DNA damage response (DDR) network, but how DDR proteins engage repressive chromatin marks is unknown. We identify the histone H3-lysine-9 methyltransferase SETDB1 as the bridge linking the DDR to silencing in male mice. At the onset of silencing, X-chromosome H3K9 trimethylation (H3K9me3) enrichment is downstream of DDR factors. Without Setdb1, the X chromosome accrues DDR proteins but not H3K9me3. Consequently, sex chromosome remodelling and silencing fails, causing germ cell apoptosis. Our data implicate TRIM28 in linking the DDR to SETDB1, and uncover additional factors with putative meiotic XY-silencing functions. Furthermore, we show that SETDB1 imposes timely expression of meiotic and post-meiotic genes. Setdb1 thus unites the DDR network, asynapsis and meiotic chromosome silencing.
2018-11-01 | GSE107671 | GEO