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Single-cell RNA-Seq of kidneys of Brg1-deficiency and wild type mice

ABSTRACT: We deleted the chromatin regulator Brg1 in Wnt4-expressing cells and FACS-purified Wnt4-lineage cells of wild-type and Brg1-deficient mouse kidneys. We then carried out single-cell RNA sequencing (scRNA-seq) to investigate the cell subpopulations and the effects of Brg1-deficiency in the differentiation of Wnt4-lineage cells. scRNA-seq analyses identify 35 clusters of Wnt4-descendant cells and uncover novel cell types and genes that have so far not been linked to Wnt4-lineage cells. Brg1-deficiency leads to increased endothelial, stromal, and smooth-muscle cells and decreased nephron tubular cells. In Brg1-deficient kidneys, the expression of Pttg1 and proliferation are increased in Wnt4-expressing precursors, which cannot transition to a characteristic tubular state and appear to undergo fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE200301 | GEO | 2022/04/08

REPOSITORIES: GEO

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Open chromatin and single-cell sequencing analysis reveals the contribution of Wnt4-lineage cells and the importance of chromatin regulators in renal tubular and interstitial differentiation

Project description:Although Wnt4 is an early marker of nephron differentiation, how Wnt4-lineage cells differentiate into the renal interstitium and other cells types is unclear. Cell fate, proliferation, migration, and differentiation are controlled by precise spatiotemporal gene expression programs that are coordinately regulated by cell-cycle, lineage-specific transcription and chromatin regulatory factors. However, little is known about the roles of epigenetic/chromatin regulators in renal tubular and interstitial differentiation and diseases. We deleted the chromatin regulator Brg1 in Wnt4-expressing cells and FACS-purified Wnt4-lineage cells of wild-type and Brg1-deficient kidneys. We then carried out assay for transposase-accessible chromatin sequencing (ATAC-seq) to determine how Brg1-deficiency alters chromatin accessibility. We further performed single-cell RNA sequencing (scRNA-seq) to define the population and the effects of Brg1-deficiency in the differentiation of Wnt4-lineage cells. Our ATAC-seq analysis shows that Brg1-deficiency alters accessibility at thousands of active enhancers harboring motifs for an array of transcription factors. Unbiased scRNA-seq analyses identify 35 clusters of Wnt4-descendant cells and uncover novel cell types and genes that have so far not been linked to Wnt4-lineage cells. Brg1-deficiency leads to increased endothelial, stromal, and smooth-muscle cells and decreased nephron tubular cells. In Brg1-deficient kidneys, the expression of Pttg1 and proliferation are increased in Wnt4-expressing precursors, which cannot transition to a characteristic tubular state and appear to undergo fibrosis. Our results provide crucial insight into chromatin remodeling events and Wnt4-lineage cell-associated gene expression dynamics, highlighting the importance of chromatin regulators in controlling the differentiation of these cells and the expression of disease-associated genes.

2022-04-08 | GSE199188 | GEO

Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury

Project description:The Hippo/YAP pathway plays a critical role in early embryonic kidney development, but its functions in the adult kidney are less well understood. Our previous work has demonstrated that tubular YAP activation induced by double knockout of the upstream Hippo kinases Mst1 and Mst2 (Mst1/2 dKO) promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Several secreted factors were found to be increased by YAP in tubular cells, but how the transcriptional network is altered by YAP is largely unknown. Here, we show that tubular YAP was already activated at 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell over-proliferation, tubular injury and renal inflammation induced by UUO or cisplatin. RNA-Seq, ChIP and luciferase assay revealed that YAP promoted the transcription of the transcription factor KLF5 whereas no interaction between YAP and KLF5 was observed. Consistently, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell over-proliferation, tubular injury and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, in which tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell over-proliferation, tubular injury and renal inflammation

2024-05-01 | GSE235443 | GEO

Tubular insulin-induced gene 1 deficiency promotes NAD+ consumption and exacerbates kidney fibrosis

Project description:<p>Profibrotic proximal tubular (PT) were identified as a unique phenotype of PTCs in renal fibrosis by single-cell RNA sequencing (scRNA-seq). Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insulin-induced gene 1 (Insig1) is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered that tubular Insig1 deficiency, rather than fibroblast Insig1 deficiency, play a detrimental role in the pathogenesis of renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Mechanistically, Insig1 deletion in PTCs boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD+ consumption and ER enlargement, as well as accelerating renal fibrosis. We also identified nicardipine as a selective inhibitor of Aldh1a1, which could restore NAD+ and maintain ER homeostasis, as well as improve renal fibrosis. Together, our findings support tubular Insig1 as a new therapeutic target for chronic kidney disease (CKD).</p>

1970-01-01 | MTBLS9985 | MetaboLights

mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress

Project description:The mechanistic target of rapamycin mTORC1 is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTOR inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By utilizing constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in counter-current multiplication and urine concentration. Although mTORC2 partially compensated the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice, and caused pronounced apoptosis, diminished proliferation rates and delayed recovery. These findings identify mTORC1 as an essential regulator of tubular energy metabolism and as a crucial component of ischemic stress responses. Pharmacological inhibition of mTORC1 likely affects tubular homeostasis, and may be particularly deleterious if the kidney is exposed to acute injury. Furthermore, the combined inhibition of mTORC1 and mTORC2 may increase the susceptibility to renal damage. Raptor fl/fl*KspCre and Raptor fl/fl animals were sacrificed at P14 before the development of an overt functional phenotype. Kidneys were split in half and immediately snap frozen in liquid nitrogen.

2014-06-09 | E-GEOD-54417 | biostudies-arrayexpress

RNA-seq analysis of dickkopf-3 knockout and C57Bl/6 mice kidneys 7 days after unilateral ureteral obstruction

Project description:Renal tubular atrophy and interstitial fibrosis are common hallmarks of etiologically different progressive chronic kidney diseases (CKD) that eventually result in organ failure. We identify Dickkopf-3 (Dkk3) as a stress-induced, tubular epithelia-derived mediator of kidney fibrosis. Genetic as well as antibody-mediated abrogation of Dkk3 led to reduced tubular atrophy and decreased interstitial matrix accumulation in two mouse models of renal fibrosis. This was accompanied by an amplified, anti-fibrogenic, inflammatory response within the injured kidney. Mechanistically, Dkk3 deficiency led to diminished canonical Wnt/β-catenin signaling in stressed tubular epithelial cells. To identify global changes in gene expression due to the lack of Dkk3, whole-transcriptome sequencing (mRNA-seq) was performed on RNA isolated from kidneys of Wt and Dkk3-/- mice 7 days after UUO.

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The aging kidney is characterized by tubuloinflammaging, a phenotype associated with MHC-II gene expression

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2023-09-11 | GSE233718 | GEO

Single-cell RNA-Seq of kidneys of Brg1-deficiency and wild type mice

Project description:Single-cell RNA-Seq of kidneys of Brg1-deficiency and wild type mice

| PRJNA824029 | ENA

Brg1 activates enhancer repertoires to establish B cell identity and modulate cell growth

Project description:Early B cell development is orchestrated by the combined activities of the transcriptional regulators E2A, EBF1, Foxo1 and Ikaros. However, how the genome-wide binding patterns of these regulators are modulated during B-lineage development remains to be determined. Here, we found that in lymphoid progenitors the chromatin remodeler Brg1 specified the B cell fate. In committed pro-B cells Brg1 regulated Igh locus contraction and controlled c-Myc expression to modulate the expression of genes that regulate ribosome biogenesis. In committed pro-B cells Brg1 also suppressed a pre-B lineage-specific pattern of gene expression. Finally, we found that Brg1 acted mechanistically to establish B cell fate and modulate cell growth by facilitating access of lineage-specific transcription factors to poised enhancer repertoires. 8 ATAC-Seq samples from sorted ALP and BLP (duplicates, control and Brg1-deleted), 4 ATAC-Seq samples from cultured pro-B cells (duplicates, control and Brg1-deleted), 2 Ikaros ChIP-seq samples (performed in Rag1-/- pro-B cells and in E2A-/- pre-pro-B cells), 1 Brg1 ChIP-seq sample and accompanying Input sample (both in Rag1-/- pro-B cells), 4 RNA-Seq samples from cultured pro-B cells (duplicates, control and Brg1-deleted), 6 RNA-Seq samples from cultured Rag1-/- pro-B cells (triplicates, control and Brg1-knock down).

2015-05-15 | E-GEOD-66978 | biostudies-arrayexpress

Cell intrinsic Wnt4 influences cDC fate determination to suppress Type 2 immunity

Project description:We demonstrate that Wnt4, a beta-catenin independent Wnt ligand, is produced by both hematopoietic and non-hematopoietic cells and is both necessary and sufficient for pre-cDC1/cDC1 maintenance. Whereas BM cDC precursors undergo phosphoJNK/c-Jun activation upon Wnt4 treatment, loss of cDC Wnt4 in CD11cCreWnt4flox/flox mice impaired differentiation of CD24+, Clec9A+, CD103+ cDC1 compared to CD11cCre controls. Conversely, sc-RNAseq analysis of BM revealed a 2-fold increase in cDC2 gene signature genes and flow cytometry demonstrated increased numbers of SIRP-α + cDC2 amid lack of Wnt4. Increased cDC2 numbers due to CD11c-restricted Wnt4 deficiency increased interleukin 5 production, group 2 innate lymphoid cell (ILC2) expansion, and host resistance to the hookworm parasite Nippostrongylus brasiliensis. Collectively, these data uncover a novel and unexpected role for Wnt4 in cDC subset differentiation and Type 2 immunity.

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Nephron progenitor commitment is a stochastic process influenced by cell migration.

Project description:Kidney development depends on a balance of nephron progenitor self-renewal and commitment. Here we examine how cells shift from a motile progenitor state to a static committed state during nephrogenesis. Cells that express Wnt4, an early marker of commitment, give rise to both the nephron lineage and a migrating sub-population that may re-enter the progenitor pool. Single cell transcriptional profiling reveals Wnt4-lineage cells across a range of transcriptional states, including cells that return to an uninduced progenitor state.

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