Vhl and Pbrm1 double deletion effect on kidney
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA326726 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3714590_1.fastq.gz | Fastqsanger.gz | |||
| SRR3714590_2.fastq.gz | Fastqsanger.gz | |||
| SRR3714600_1.fastq.gz | Fastqsanger.gz | |||
| SRR3714600_2.fastq.gz | Fastqsanger.gz | |||
| SRR3714610_1.fastq.gz | Fastqsanger.gz |
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Project description:To determine why double deficiency of Vhl and Pbrm1 but not single deficiency of either gene resulted in ccRCC, we performed gene expression profiling of RNA isolated from renal cortices of 3-month-old WT, VhlF/FKsp-Cre, Pbrm1F/FKsp-Cre, and VhlF/FPbrm1F/FKsp-Cre mice.
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Project description:CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1 and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard of care agent, axitinib. RNAseq analysis was utilized to evaluate the expression profile produced by the targeted loss of Vhl, Pbrm1, Keap1 and Tsc1 in these mouse tumors. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2-independent.
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Project description:PBRM1 encodes an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and the inactivation of PBRM1 is the second most frequent mutational event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodeling, especially pertaining to kidney tumorigenesis, has not been well examined. Here we show that in VHL-deficient renal tumors, PBRM1 deficiency results in aberrant PBAF complexes that localize to de novo genomic loci and activate the pro-tumorigenic NF-?B pathway. PBRM1-deficient PBAF complexes, despite retaining the association between SMARCA4 and ARID2, have loosely tethered BRD7 and redistribute from promoter proximal regions to distal enhancers containing NF-?B motifs. Subsequently, PBRM1-deficient cells display heightened NF-?B activity in multiple models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of both pre-existing and newly acquired RELA specific to PBRM1 loss, and activates downstream target gene expression. Proteasome inhibitor bortezomib reverses NF-?B activation by reducing RELA occupancy and delays growth of PBRM1-deficient tumors. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-?B target genes by residual PBRM1-deficient PBAF complexes.
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Project description:PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler. The inactivation of PBRM1 is the second most frequent mutational event in kidney tumorigenesis. Here we show that in VHL-deficient ccRCC tumors, PBRM1 loss results in an altered PBAF complex that retains the association between SMARCA4 and ARID2 but disengages BRD7 from SMARCA4. The PBRM1-deficient PBAF complexes redistribute from promoter proxy regions to distal enhancer regions. The ATPase function of SMARCA4 enhances the recruitment of nuclear factor RELA to aberrant sites and promotes NF-κB activity. Proteasome inhibitor bortezomib reverses NF-κB activation by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.
2023-02-13 | GSE152734 | GEO
Project description:To establish the role of proximal tubular hypoxia in diabetic kidney disease, we use a mouse line with a specific deletion of von-Hippel-Lindau (VHL) in the proximal tubule and treat them with streptozotocin (STZ) to induce a type I diabetes mellitus. 10 weeks after induction of diabetes mellitus samples were collected.
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Project description:PBRM1 encodes an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and the inactivation of PBRM1 is the second most frequent mutational event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodeling, especially pertaining to kidney tumorigenesis, has not been well examined. Here we show that in VHL-deficient renal tumors, PBRM1 deficiency results in aberrant PBAF complexes that localize to de novo genomic loci and activate the pro-tumorigenic NF-κB pathway. PBRM1-deficient PBAF complexes, despite retaining the association between SMARCA4 and ARID2, have loosely tethered BRD7 and redistribute from promoter proximal regions to distal enhancers containing NF-κB motifs. Subsequently, PBRM1-deficient cells display heightened NF-κB activity in multiple models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of both pre-existing and newly acquired RELA specific to PBRM1 loss, and activates downstream target gene expression. Proteasome inhibitor bortezomib reverses NF-κB activation by reducing RELA occupancy and delays growth of PBRM1-deficient tumors. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.
2023-02-13 | GSE222245 | GEO
Project description:PBRM1 encodes an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and the inactivation of PBRM1 is the second most frequent mutational event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodeling, especially pertaining to kidney tumorigenesis, has not been well examined. Here we show that in VHL-deficient renal tumors, PBRM1 deficiency results in aberrant PBAF complexes that localize to de novo genomic loci and activate the pro-tumorigenic NF-κB pathway. PBRM1-deficient PBAF complexes, despite retaining the association between SMARCA4 and ARID2, have loosely tethered BRD7 and redistribute from promoter proximal regions to distal enhancers containing NF-κB motifs. Subsequently, PBRM1-deficient cells display heightened NF-κB activity in multiple models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of both pre-existing and newly acquired RELA specific to PBRM1 loss, and activates downstream target gene expression. Proteasome inhibitor bortezomib reverses NF-κB activation by reducing RELA occupancy and delays growth of PBRM1-deficient tumors. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.
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Project description:PBRM1 is the 2nd-most frequently inactivated gene in clear cell renal cell cancer (RCC) but the oncogenic mechanisms, and hence methods for correction, are unclear. PBRM1 is a subunit of the PBAF coactivator complex that transcription factors use to reposition nucleosomes (‘open chromatin’) for gene activation. We therefore looked for transcription factors that recruit endogenous PBRM1 in kidney lineage/RCC cells, as a waypoint to identifying pathways impacted by PBRM1 loss. Unbiased immunoprecipitation/mass-spectrometry analyses of the endogenous PBRM1 interactome in kidney lineage cells revealed PAX8, a master transcription factor essential for proximal tubule epithelial fates, as the major transcription factor recruiting PBRM1/PBAF. The reverse analyses of the PAX8 interactome confirmed recruitment specifically of PBRM1/PBAF, and not the functionally similar BAF coactivator complex. More conspicuous in the PAX8 hub in RCC cells, however, were several corepressors, e.g. DNMT1, which oppose coactivators to repress instead of activate genes. Accordingly, key PAX8 target genes, e.g., GATA3, LHX1, WT1, and ~1000 other downstream kidney epithelial genes, but not PAX8 or PAX2, demonstrated loss of the histone lysine 27 acetylation (H3K27ac) activation mark, increase in CpG methylation repression marks, and lower expression in RCC vs normal kidney cortex, with the greatest repression in cases with bi-allelic PBRM1 inactivation. PBRM1 re-introduction into RCC cells, or depletion of the corepressor DNMT1 using siRNA or a clinical drug decitabine, rebalanced composition and function of the PAX8 transcription factor hub to coactivators, to thereby activate terminal epithelial-fates in vitro and in vivo. In sum, PBRM1 loss in RCC cells skews coregulator composition of the PAX8 master transcription factor hub toward corepressors and repression instead of activation of the downstream terminal epithelial-program; this oncogenic action could be reversed by pharmacologic corepressor depletion/inhibition.
2022-02-16 | PXD020544 | Pride