MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD009338
PROVIDER: PRJNA433925 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6714670.fastq.gz | Fastqsanger.gz | |||
| SRR6714680.fastq.gz | Fastqsanger.gz | |||
| SRR6714690.fastq.gz | Fastqsanger.gz | |||
| SRR6714671.fastq.gz | Fastqsanger.gz | |||
| SRR6714681.fastq.gz | Fastqsanger.gz |
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Project description:MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins. Functional investigation of 128 conserved MLL-fusion-interactors identified a specific role for the lysine methyltransferase SETD2 in MLL-leukemia. SETD2 loss caused growth arrest and differentiation of AML cells, and led to increased DNA damage. In addition to its role in H3K36 tri-methylation, SETD2 was required to maintain high H3K79 di-methylation and MLL-AF9 binding to critical target genes, such as Hoxa9. SETD2 loss synergized with pharmacologic inhibition of the H3K79 methyltransferase DOT1L to induce DNA damage, growth arrest, differentiation and apoptosis. These results uncover a dependency for SETD2 during MLL-leukemogenesis, revealing a novel actionable vulnerability in this disease.
2018-05-23 | GSE110521 | GEO
Project description:MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins. Functional investigation of 128 conserved MLL-fusion-interactors identifies a specific role for the lysine methyltransferase SETD2 in MLL-leukemia. SETD2 loss causes growth arrest and differentiation of AML cells, and leads to increased DNA damage. In addition to its role in H3K36 tri-methylation, SETD2 is required to maintain high H3K79 di-methylation and MLL-AF9-binding to critical target genes, such as Hoxa9. SETD2 loss synergizes with pharmacologic inhibition of the H3K79 methyltransferase DOT1L to induce DNA damage, growth arrest, differentiation, and apoptosis. These results uncover a dependency for SETD2 during MLL-leukemogenesis, revealing a novel actionable vulnerability in this disease.
| S-EPMC5959866 | biostudies-literature
Project description:SETD2 is a methyltransferase critical for the integrity of epithelial barrier. However, the role of SETD2 in safeguarding epithelial barrier integrity remains largely unexplored. Here, we performed proteomics analysis on intact intestinal barrier with SETD2 present and compromised intestinal barrier with SETD2 loss. To characterize biological responses triggered by SETD2 deletion in compromised intestinal barrier at the protein level, we conducted global proteomics studies.
2026-04-06 | PXD055747 | Pride
Project description:Blood vessel-resident macrophages safeguard blood and vessel integrity in zebrafish
| PRJNA1260425 | ENA
Project description:Macrophages are essential in immune defence, tissue development, and disease onset and progression. Their function is in part dictated by their microenvironment and origin. Tissue-resident macrophages originate from yolk sac progenitors, persisting in adult organs and tissues mainly through self-renewal. Although ubiquitously present throughout the body, no dedicated macrophage population is known to function within the vast network of blood vessels, despite the importance of maintaining a healthy vascular and blood system. Here, we identified a distinctive population of macrophages residing within blood vessels, which we termed blood-resident macrophages (bMΦ). bMΦ actively survey the blood to eliminate foreign particles and unfit cells, and act as the first responders to endothelial damage. bMΦ emerge directly from the main axial vessels of zebrafish embryos though an atypical endothelial-to-macrophage transition (EMacT), independent of Runx1 and Csf1r, both essential for hematopoietic stem cell and myeloid cell production, respectively. Our data thus unveil the existence of a specialized population of macrophages that function within the confinement of the vasculature to safeguard blood from foreign threats and maintain blood vessel integrity. These discoveries not only expand our understanding of immune surveillance mechanisms but also offer potential avenues for the treatment of bloodborne diseases and vascular injuries.
2026-03-11 | PXD052344 | Pride
Project description:Protein abundance does not necessarily correlate with mRNA levels, highlighting the highly variable efficiency of translation. Ribosome biogenesis, the process of ribosome production, affects translation efficiency and plays a crucial role in various biological processes. However, its role in maintaining epithelial barrier integrity has not been definitively established. SETD2 is a methyltransferase critical for the integrity of epithelial barrier. Here, we examined intact intestinal barrier with SETD2 present and compromised intestinal barrier with SETD2 loss.
2024-10-01 | GSE276958 | GEO
Project description:Histone-Lysine N-methyltransferase SETD2 is an evolutionarily conserved histone methyltransferase that associates with RNA Polymerase II (RNAPII) and catalyzes trimethylation of histone H3 lysine 36 (H3K36me3) in transcribed regions. Interestingly, SETD2 is frequently mutated in cancers. Clear cell renal cell carcinomas (ccRCCs) have extensive mutation of SETD2, implicating SETD2 as a tumor suppressor. ccRCCs are known for early driving events where the 3p chromosomal arm is lost, deleting one copy of SETD2, resulting in haploinsufficiency. While the role of SETD2 mediated H3K36me3 and interaction of RNAPII has been the focus of many studies, haploinsufficient SETD2 tumors retain H3K36me3, yet have drastic genome stability defects. The C-terminus of SETD2 is required for H3K36me3 while the N-terminus of SETD2 remains poorly characterized compared to the C-terminus. The N-terminus is highly disordered and has recently been shown to contribute to SETD2 stability, implicating regulatory functions. To better understand how SETD2 contributes to chromatin biology, we first sought to identify SETD2 protein interactors. A stable, immortalized normal human kidney epithelial cell (HKC) line with a dox inducible SETD2-APEX2 construct was used for a proximity-based biotinylation assay. Initial analysis yielded 2083 biotinylated proteins with significant enrichment (log2 fold change > 2 p-value < 0.05) in SETD2-APEX2 compared to control. Gene Ontology analysis of these interactors revealed enrichment of proteins involved in nuclear envelope functions, including lamin A/C, lamin B1, lamin B2 and emerin. These interactions were confirmed via western and reciprocal immunoprecipitation (IP). To determine effect of SETD2 depletion on lamin A/C and lamin B1 phosphorylation, we performed lamin A/C or lamin B1 IP from control or SETD2-knockdown (KD) cells and interrogated via LC-MS/MS. Mass spectrometry analysis revealed a significant decrease in lamin A/C S22 phosphorylation, and modest decrease in S390 phosphorylation, in SETD2 depleted cells compared to controls. While lamin B1 S23 phosphorylation was detected in control cells, we did not detect it in SETD2-KD cells, indicating a significant reduction in S23 phosphorylation upon SETD2 depletion. Next, we sought to identify the effect of SETD2 N-terminal deletion on the SETD2 protein interactome. We compared the protein interactors of dox inducible WT-SETD2 APEX2 fusion to an N-terminal deletion mutant of SETD2 (tSETD2-APEX2). Deletion of the N-terminus resulted in loss of lamin B1 and emerin interaction. Intriguingly, tSETD2 selectively associated with lamin C, whereas WT SETD2 interacted with both lamin A and C. These data together reveal an interaction with SETD2 and nuclear lamins. Further experiments revealed a role for the SETD2 N-terminus in facilitating the association of lamins with CDK1, thereby promoting lamin phosphorylation and depolymerization required for nuclear envelope disassembly during mitosis. Together, the data reveal a non-catalytic role of SETD2 during mitosis.
2025-06-04 | PXD040771 | Pride
Project description:Macrophages are essential in immune defence, tissue development and maintenance, and are involved in disease onset and progression. Their function is influenced by their microenvironment and origin. While tissue-resident macrophages originate from yolk sac progenitors and persist in some adult tissues through self-renewal, no dedicated macrophage population is known to function within the vast network of blood vessels, despite the importance of maintaining a healthy vascular and blood system. Here, using high spatiotemporal live imaging of zebrafish embryos, we identified a distinctive population of macrophages residing within blood vessels, which we term blood vessel-resident macrophages (bMs). bMs actively survey the bloodstream, clearing foreign particles and unfit cells, and are the first responders to endothelial damage. bMs emerge directly from axial vessels through an atypical endothelial-to-macrophage transition (EMacT), independent of Runx1 and Csf1r, both essential for hematopoiesis and myelopoiesis, respectively. We further demonstrate that bMs are evolutionary conserved in mice. Our data thus unveil the existence of a specialized population of macrophages that function within the vasculature to safeguard blood from foreign threats and maintain blood vessel integrity. These discoveries broaden our understanding of immune surveillance, opening new avenues for treating bloodborne and vascular diseases.
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Project description:ZEB2 orchestrates a transcriptional program to safeguard the integrity of human CD4+ Th1 EM cells
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Project description:RNA sequencing of SETD2 isogenic renal cell carcinoma cell lines. Examination of RNA expression in SETD2 isogenic cell lines
2015-06-17 | E-GEOD-66879 | biostudies-arrayexpress