Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA448165 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6920790.fastq.gz | Fastqsanger.gz | |||
| SRR6920791.fastq.gz | Fastqsanger.gz | |||
| SRR6920792.fastq.gz | Fastqsanger.gz | |||
| SRR6920793.fastq.gz | Fastqsanger.gz |
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Project description:SET domain containing 2 (Setd2), encoding a histone methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we described an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelet accompanied with hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation, because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit of quiescence and commit to differentiation, which lead to hematopoietic stem cells exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes including Myc. Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of HSCs through restricting the NSDs/SEC mediated RNA Polymerase II elongation.
2018-05-01 | GSE112550 | GEO
Project description:SET domain containing 2 (Setd2), encoding a histone methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we describe an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelets accompanied by hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit from quiescence and commit to differentiation, which lead to hematopoietic stem cell exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes, including Myc Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of hematopoietic stem cells through restricting the NSDs/SEC mediated RNA polymerase II elongation.
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Project description:H3K36me3 is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occurs co-transcriptionally when the methyltransferase SETD2 associates with RNA polymerase II. Using electron microscopy assisted by protein-protein crosslinking mass spectrometry, we solved three cryo-EM structures of SETD2 bound to Pol II elongation complexes at different states of nucleosome passage. Together with functional probing, our results suggest a 3-step mechanism of transcription-coupled H3K36me3 deposition. First, binding to the elongation factor SPT6 tethers the catalytic SET domain in proximity to the upstream DNA. Second, Pol II nucleosome passage leads to the transfer of a hexasome from downstream to upstream, poised for methylation. Finally, continued transcription leads to upstream nucleosome reassembly, partial dissociation of the histone chaperone FACT and sequential methylation of both H3 tails, completing H3K36me3 deposition of an upstream nucleosome after RNA polymerase II passage.
2025-09-18 | PXD067197 | Pride
Project description:Senataxin Promotes RNA Polymerase II Elongation [RChIPseq]
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Project description:Senataxin Promotes RNA Polymerase II Elongation [Hap1_DRBrelease_TTseq]
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Project description:Senataxin Promotes RNA Polymerase II Elongation [Hap1_TTseq]
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Project description:Senataxin Promotes RNA Polymerase II Elongation [TTseq]
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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