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Dose escalation of Wnt stimulation during the exit from pluripotency identifies tranilast as a small molecule regulator of cardiac mesoderm differentiation (RNA-Seq)

ABSTRACT: Wnt signalling is a critical determinant of cell lineage development. This study used Wnt dose-dependent induction programs to gain insights into molecular regulation of stem cell differentiation. We performed single cell RNA-sequencing of cells responding to a dose-escalation protocol with Wnt agonist CHIR-99021 during the exit from pluripotency to identify cell types and genetic activity driven by Wnt stimulation. Results of activated gene sets and cell types were then used to build a multiple regression model that predicts the efficiency of cardiomyocyte differentiation. Cross-referencing Wnt-associated gene expression profiles to the Connectivity Map database, we identified a novel property of the small molecule drug, tranilast. We found that tranilast synergistically activates Wnt signalling to promote cardiac lineage differentiation which we validate in vitro and in vivo. Our study provides an integrated workflow that links experimental datasets, prediction models and small molecule databases to identify novel drug-like compounds that control cell differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246079 | GEO | 2024/01/19

REPOSITORIES: GEO

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Dose escalation of Wnt stimulation during the exit from pluripotency identifies tranilast as a small molecule regulator of cardiac mesoderm differentiation (scRNA-Seq)

Project description:Wnt signalling is a critical determinant of cell lineage development. This study used Wnt dose-dependent induction programs to gain insights into molecular regulation of stem cell differentiation. We performed single cell RNA-sequencing of cells responding to a dose-escalation protocol with Wnt agonist CHIR-99021 during the exit from pluripotency to identify cell types and genetic activity driven by Wnt stimulation. Results of activated gene sets and cell types were then used to build a multiple regression model that predicts the efficiency of cardiomyocyte differentiation. Cross-referencing Wnt-associated gene expression profiles to the Connectivity Map database, we identified a novel property of the small molecule drug, tranilast. We found that tranilast synergistically activates Wnt signalling to promote cardiac lineage differentiation which we validate in vitro and in vivo. Our study provides an integrated workflow that links experimental datasets, prediction models and small molecule databases to identify novel drug-like compounds that control cell differentiation.

2024-01-19 | GSE246080 | GEO

Dose escalation of Wnt stimulation during the exit from pluripotency identifies tranilast as a small molecule regulator of cardiac mesoderm differentiation (ATAC-Seq)

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RNA-sequencing of human pluripotent stem-cell derived endothelial cells under control and Wnt-activating conditions

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High levels of canonical Wnt signaling lead to loss of stemness and increased differentiation in hematopoietic stem cells

Project description:Canonical Wnt signalling regulates the self-renewal of most if not all stem cell systems. In the blood system, the role of Wnt signalling has been subject of much debate, with positive and negative roles of Wnt signalling proposed for hematopoietic stem cells (HSC). As we have shown previously, this controversy can be largely explained by the effects of different dosages of Wnt signalling. What remained unclear however, was why high Wnt signals would lead to loss of reconstituting capacity. To better understand this phenomenon, we have taken advantage of a series of hypomorphic mutant Apc alleles resulting in a broad range of Wnt dosages in HSCs, purified those HSCs and performed whole genome gene expression analyses. Gene expression profiling and functional studies show that HSCs with APC mutations lead to high Wnt levels , enhanced differentiation and diminished proliferation, but have no effect on apoptosis, collectively leading to loss of stemness. Thus, we provide mechanistic insight into the role of APC mutations and Wnt signalling in HSC biology. As Wnt signals are explored in various in vivo and ex vivo expansion protocols for HSCs, our findings also have clinical ramifications. To investigate the effects of Wnt signals in hematopoietic cells, mice carrying floxed Apc or hypomorphic Apc mutants were crossed, LSK cells were isolated and treated with Cre IRES GFP gamma-retrovirus ex vivo, GFP+ cells were sorted and RNA expression was determined.

2016-03-23 | E-GEOD-79495 | biostudies-arrayexpress

Single-cell SLAM-seq profiling of normal and tumor organoids

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High levels of canonical Wnt signaling lead to loss of stemness and increased differentiation in hematopoietic stem cells

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Canonical Wnt signalling regulates nuclear export of Setdb1 during skeletal muscle terminal differentiation [ChIP-seq]

Project description:The histone 3 lysine 9 (H3K9)-specific methyltransferase (KMT) Setdb1 is essential for both stem cell pluripotency and terminal differentiation of different cell types. To shed light on Setdb1 role(s) in these mutually exclusive processes, we used mouse skeletal myoblasts as a model of terminal differentiation. Ex vivo studies on isolated single myofibres showed that Setdb1 is required for muscle adult stem cells expansion following activation and in vitro studies on skeletal myoblasts confirmed that Setdb1 suppresses terminal myoblast differentiation. We used genome-wide analyses to identify Setdb1 direct target genes in myoblasts and observed a release of Setdb1 from the promoter of selected target genes upon myoblast terminal differentiation, concomitant to a nuclear export of Setdb1 to the cytoplasm. We demonstrated that both genomic release and cytoplasmic Setdb1 relocalisation during differentiation were dependent on canonical Wnt signalling. Taken together, our findings uncover a functional link between Setdb1 and canonical Wnt signalling in skeletal muscle cells, which affects the expression of a subset of Setdb1 target genes. We revealed Wnt-dependent subcellular relocalisation of Setdb1 as a novel mechanism regulating Setdb1 functions. ChIP-seq of Setdb1 and H3K9me3 in Myoblast cells (C2C12)

2016-02-01 | E-GEOD-65493 | biostudies-arrayexpress

Canonical Wnt pathway controls mESCs self-renewal through inhibition of spontaneous differentiation via β-catenin/TCF/LEF functions

Project description:The Wnt/β-catenin signalling pathway is a key regulator of embryonic stem cell self-renewal and differentiation. Constitutive activation of this pathway has been shown to significantly increase mouse embryonic stem cell (mESC) self-renewal and pluripotency marker expression. In this study, we generated a novel β-catenin knock-out model in mESCs by using CRISPR/Cas9 technology to delete putatively functional N-terminally truncated isoforms observed in previous knock-out models. While we showed that aberrant N-terminally truncated isoforms are not functional in mESCS, we observed that canonical Wnt signalling is not active in mESCs, as β-catenin ablation does not alter mESC transcriptional profile in LIF-enriched culture conditions; on the other hand, Wnt signalling activation represses mESC spontaneous differentiation. We also showed that transcriptionally silent β-catenin (ΔC) isoforms can rescue β-catenin knock-out self-renewal defects in mESCs, cooperating with TCF1 and LEF1 in the inhibition of mESC spontaneous differentiation in a Gsk3 dependent manner.

2020-01-10 | GSE143340 | GEO

Change in transcriptome upon G9a knockdown in RD ERMS (Embryonal Rhabdomyosarcoma) cells

Project description:The Wnt signaling pathway is down-regulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of myogenic differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way towards novel therapeutic modalities. In this study, we demonstrate that the lysine methyltransferase G9a suppresses the canonical Wnt signalling pathway by activating expression of the Wnt antagonist DKK1. Inhibition of G9a expression or activity reduced DKK1 expression and elevated canonical Wnt signalling resulting in myogenic differentiation in vitro and in vivo. Mechanistically, G9a impacted Sp1 and p300 enrichment at the DKK1 promoter in a methylation-dependent manner. The reduced tumor growth upon G9a deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among thirteen drugs targeting chromatin modifiers, G9a inhibitors were highly effective in reducing ERMS cell viability. Together, our study demonstrates that ERMS cells are vulnerable to G9a inhibitors and suggest that targeting the G9a-DKK1--catenin node holds promise for differentiation therapy.

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Project description:We compared a transcriptome of hESC line VUB04 which has a low differentiation propensity towards definitive endoderm with transcriptomes of control hESC lines at the undifferentiated stage and after the 24-hour differentiation towards mesendoderm. The results showed that endogenous suppression of WNT signalling in VUB04 results in an inefficient switch from self-renewal to commitment during the definitive endoderm differentiation. Subsequenlty, we demonstrated that this differentiation disruption can be overcome by increasing the WNT stimulation or by inhibiting the PI3K/AKT signalling at the onset of differentiation.

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