YAP/TAZ activity in PDGFRa-expressing alveolar fibroblasts modulates lung fibroblast-epithelial cell crosstalk through Wnt4 [scATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA1234570 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32651045_1.fastq.gz | Fastqsanger.gz | |||
| SRR32651045_2.fastq.gz | Fastqsanger.gz | |||
| SRR32651046_1.fastq.gz | Fastqsanger.gz | |||
| SRR32651046_2.fastq.gz | Fastqsanger.gz | |||
| SRR32651047_1.fastq.gz | Fastqsanger.gz |
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Project description:The Hippo signaling pathway, mediated by its transcriptional effectors YAP and TAZ, play vital roles in maintaining lung homeostasis and facilitating injury repair. While the roles of the Hippo pathway in epithelial cells are well-established, its regulatory effects on lung fibroblasts remain less understood. Here, we engineered a novel mouse allele to allow inducible knockdown of YAP and TAZ, and show that fibroblast-specific knockdown enhances the ability of PDGFRa+ alveolar fibroblasts to support organoids derived from alveolar epithelial stem cells in vitro. Single-cell multiomic profiling revealed changes in fibroblast subpopulations, including the emergence of an Mmp9+ cluster containing Wnt4+ cells. Analyses demonstrated shifts in the epigenomic landscape leading to varied enrichment of transcription factor motifs across both fibroblasts and epithelial cells in response to targeted suppression of YAP/TAZ in fibroblasts. Further computational analyses identified an increase in epithelial Wnt signaling which was confirmed by in vivo studies. We found that Wnt4 expression was increased in PDGFRa-lineage+ fibroblasts and enhanced proliferation of SPC+ AT2 cells following fibroblast-specific YAP/TAZ knockdown. These results shed new light on the mechanistic role of YAP/TAZ in PDGFRa+ alveolar fibroblasts in supporting AT2 cell maintenance and proliferation via Wnt4 secretion.
2025-04-10 | GSE291640 | GEO
Project description:The Hippo signaling pathway, mediated by its transcriptional effectors YAP and TAZ, play vital roles in maintaining lung homeostasis and facilitating injury repair. While the roles of the Hippo pathway in epithelial cells are well-established, its regulatory effects on lung fibroblasts remain less understood. Here, we engineered a novel mouse allele to allow inducible knockdown of YAP and TAZ, and show that fibroblast-specific knockdown enhances the ability of PDGFRa+ alveolar fibroblasts to support organoids derived from alveolar epithelial stem cells in vitro. Single-cell multiomic profiling revealed changes in fibroblast subpopulations, including the emergence of an Mmp9+ cluster containing Wnt4+ cells. Analyses demonstrated shifts in the epigenomic landscape leading to varied enrichment of transcription factor motifs across both fibroblasts and epithelial cells in response to targeted suppression of YAP/TAZ in fibroblasts. Further computational analyses identified an increase in epithelial Wnt signaling which was confirmed by in vivo studies. We found that Wnt4 expression was increased in PDGFRa-lineage+ fibroblasts and enhanced proliferation of SPC+ AT2 cells following fibroblast-specific YAP/TAZ knockdown. These results shed new light on the mechanistic role of YAP/TAZ in PDGFRa+ alveolar fibroblasts in supporting AT2 cell maintenance and proliferation via Wnt4 secretion.
2025-04-10 | GSE291641 | GEO
Project description:YAP/TAZ activity in PDGFRa-expressing alveolar fibroblasts modulates lung fibroblast-epithelial cell crosstalk through Wnt4 [scRNA-seq]
| PRJNA1234571 | ENA
Project description:Taz protects aged hematopoietic stem cells from exhaustion [scATAC-seq]
| PRJNA661357 | ENA
Project description:To find the differences between β cells expressing Wnt4 and those that do not express it (or express it at low levels) at neonatal stage, murine islets at postnatal day 1 (P1) were collected. Based on a reporter expressing Cre recombinase from the Wnt4 locus, we observed that Wnt4 expression starts in a small subset of β cells at embryonic day (E) 18.5. At neonatal stages, around 50% of β cells express Wnt4 at P0 and most of cells express it by P5. We collected Wnt4 high and Wnt4 low islet cells by FACS and compared their gene expression profile. Wnt4 high islet cell population showed a significant increase of β-cell maturation and function related genes, including transcription factors such as Pdx1 and Nkx6.1, insulin 2, glucokinase (Gck), and the glucose transporter Slc2a2. On the contrary, Wnt4 low islet cell population showed significant increasing of proliferation markers such as Pcna, Mki67 and the positive cell cycle regulators Ccnd1, Ccnd3, Ccna2, Cdk1, Cdk2 and Cdk6. Taken together, these results show that Wnt4 expression is higher in more mature but less proliferative β cells.
2022-08-02 | GSE210237 | GEO
Project description:The circulating leukocyte population contains a fraction of cells derived from progenitors that had transient PDGFRa expression during embryonic development (PDGFRa-lineage). During inflammation, extravasated leukocytes in inflamed tissue modify the tissue-resident leukocyte population and crosstalk with the stromal cells. The current study investigates the effects of extravasated leukocytes derived from PDGFRa-lineage origin on the skin in atopic dermatitis (AD). Lineage- bone marrow progenitors were isolated from PDGFRa-lineage labeling mice which labels cells derived from PDGFRa-lineage with tdTomato. Progenitors derived from PDGFRa-lineage or non-PDGFRa-lineage were transplanted to irradiated EGFP-transgenic mice and allowed for bone marrow reconstitution (BMT). AD was then induced by repeated topical application of MC903 for six times. On day 14, RNA was isolated from inflamed skin to construct library for bulk RNA sequencing. AD skin transcriptomes of PDGFRa-lineage and non-PDGFRa-lineage BMTs were compared. In addition, the obtained dataset were paired with flow cytometric measurement of leukocyte extravasation to compare samples with similar extravasation loads. We found via functional enrichment analyses that extravasated PDGFRa-lineage leukocytes possess intrinsic properties that differ from non-PDGFRa-lineage, coordinate stronger inflammatory responses and modulate the extracellular matrix.
2022-07-27 | GSE166854 | GEO
Project description:To study the physiological role of WNT4 in the postnatal ovary, a mouse strain bearing a floxed Wnt4 allele was created and mated to the Amhr2tm3(cre)Bhr strain to target deletion of Wnt4 to granulosa cells. Wnt4flox/-;Amhr2tm3(cre)Bhr/+ mice had significantly reduced ovary weights and produced smaller litters (P<0.05). Serial follicle counting demonstrated that, while Wnt4flox/-;Amhr2tm3(cre)Bhr/+ mice were born with a normal ovarian reserve and maintained normal numbers of small follicles until puberty, they had only 25.2% of the normal number of healthy antral follicles. Some Wnt4flox/-;Amhr2tm3(cre)Bhr/+ mice had no antral follicles or corpora lutea and underwent premature follicle depletion. RTPCR analyses of Wnt4flox/-;Amhr2tm3(cre)Bhr/+ granulosa cells and cultured granulosa cells that overexpress WNT4 demonstrated that WNT4 regulates the expression of Star, Cyp11a1 and Cyp19, steroidogenic genes previously identified as downstream targets of the WNT signaling effector CTNNB1. WNT4- and CTNNB1-overexpressing cultured granulosa cells were analyzed by microarray for alterations in gene expression, which showed that WNT4 also regulates a series of genes involved in late follicle development and the cellular stress response via the WNT/CTNNB1 signaling pathway. Together, these data indicate that WNT4 is required for normal antral follicle development, and may act by regulating granulosa cell functions including steroidogenesis.
2009-10-23 | GSE18704 | GEO
Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.
2014-04-02 | E-GEOD-56445 | biostudies-arrayexpress
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.
2019-08-01 | GSE131569 | GEO
Project description:Our laboratory's interest is in understanding the molecular principles that underlie the regional organization of the mammalian metanephric kidney. Our goal is to generate a detailed spatial map of the cellular expression of selected regulatory genes during mammalian kidney development. The goal of this study is to identify a population of genes that are enriched in the renal vesicle (RV) and its derivatives using Wnt4 mutants. Experiment Overall Design: Wnt4 is required for renal vesicle (RV) induction. Therefore, RV and the derivatives (s-shaped body and eventually the mature nephron) are missing in Wnt4 mutants. At E14.5, these structures are present in wildtype kidneys. Transcriptional profile comparison between E14.5 wildtype and Wnt4 mutants therefore identify genes expressed in the RV and derivatives. Minimally pooled kidney samples were used as single biological replicates. Total RNA was isolated from these pools and subjected to a single round of amplification for use on Affymetrix arrays.
2008-06-14 | E-GEOD-6288 | biostudies-arrayexpress