Single nucleus RNA sequencing of mosiac Pax2 and Pax8 mutant proximal tubules
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE278289 | GEO | 2024/11/15
REPOSITORIES: GEO
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Project description:Background: The mammalian kidneys maintain salt and water homeostasis for proper electrolyte balance and hydration. As the glomerular filtrate passes through the nephron and into the renal medulla, electrolytes, water, and urea are reabsorbed through the concerted actions of solute carrier channels and aquaporins located at various positions along the nephron and in the outer and inner medulla. Renal epithelial cells develop from Pax2 positive proliferating stem cells that suppress Pax2 expression once differentiated into mature proximal and distal tubules, but continue to express the related Pax8 protein. The collecting tubules and renal medulla are derived from a Pax2 positive ureteric bud epithelia that continue to express Pax2 and Pax8 in adult kidneys. Despite the necessity for Pax2 in renal development, functions for Pax2 or Pax8 in adult renal epithelia have not been established. Methods: In this report, we deleted either Pax2, Pax8, or both genes in adult mice and examined the phenotypes and changes in gene expression patterns. The mechanism of Pax8 mediated activation of potential target genes was described in inner medullary collecting duct cells. Results: Mice with induced deletions of both Pax2 and Pax8 exhibit severe polyuria that can be attributed to significant changes in the expression of solute carriers, such as the urea transporter UTA1, and aquaporins within the inner and outer medulla. Furthermore, Pax8 expression is induced by high salt in collecting duct cells and activates the UTA1 gene by recruiting a histone methyltransferase complex to the promoter. Conclusions: These data uncover novel functions for Pax proteins, in adult renal epithelia, that are essential for retaining water and concentrating urine.
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Project description:Dent disease has multiple defects attributed to proximal tubule malfunction including low molecular weight proteinuria, aminoaciduria, phosphaturia and glycosuria. In order to understand the changes in kidney function of the Clc5 transporter gene knockout mouse model of Dent disease, we examined gene expression profiles from proximal tubules of mouse kidneys. Overall 720 genes are expressed differentially in the proximal tubules of the Dent Clcn5 knockout mouse model compared to those of control wild type mice. The fingerprint of these gene changes may help us to understand the phenotype of Dent disease. Keywords: gene knockout, mouse, Clcn5, Dent's disease
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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.
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