ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA645927 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12211771_1.fastq.gz | Fastqsanger.gz | |||
| SRR12211771_2.fastq.gz | Fastqsanger.gz | |||
| SRR12211772_1.fastq.gz | Fastqsanger.gz | |||
| SRR12211772_2.fastq.gz | Fastqsanger.gz | |||
| SRR12211773_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 45 |
Similar Datasets
Project description:Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in the mouse identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development. We hypothesized that ASCL2 is a critical and conserved regulator of invasive trophoblast lineage development. In contrast to the mouse, the rat possesses deep intrauterine trophoblast cell invasion and spiral artery remodeling similar to human placentation. In this report, we investigated invasive/extravillous trophoblast (EVT) cell differentiation using human trophoblast stem (TS) cells and a loss-of-function mutant Ascl2 rat model. ASCL2 transcripts are expressed in the EVT column and junctional zone, which represent tissue sources of invasive trophoblast progenitor cells within human and rat placentation sites, respectively. Differentiation of human TS cells into EVT cells resulted in significant upregulation of ASCL2 and several other transcripts indicative of EVT cell differentiation. Disruption of ASCL2 impaired EVT cell differentiation as indicated by cell morphology and transcript profiles. RNA sequencing analysis of ASCL2-deficient trophoblast cells identified both downregulation of EVT cell-associated transcripts and upregulation of syncytiotrophoblast-associated transcripts, indicative of dual activating and repressing functions. ASCL2 deficiency in the rat impacted placental morphogenesis resulting in junctional zone dysgenesis and failed intrauterine trophoblast cell invasion. ASCL2 acts as a critical and conserved regulator of invasive trophoblast cell lineage development and a species-specific modulator of the syncytiotrophoblast lineage.
2021-03-01 | GSE154350 | GEO
Project description:Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast cell invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in mice identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development. We hypothesized that ASCL2 is a critical and conserved regulator of invasive trophoblast cell lineage development. In contrast to the mouse, the rat possesses deep intrauterine trophoblast cell invasion and spiral artery remodeling similar to human placentation. In this study, we investigated invasive/extravillous trophoblast (EVT) cell differentiation using human trophoblast stem (TS) cells and a loss-of-function mutant Ascl2 rat model. ASCL2 transcripts are expressed in the EVT column and junctional zone, which represent tissue sources of invasive trophoblast progenitor cells within human and rat placentation sites, respectively. Differentiation of human TS cells into EVT cells resulted in significant up-regulation of ASCL2 and several other transcripts indicative of EVT cell differentiation. Disruption of ASCL2 impaired EVT cell differentiation, as indicated by cell morphology and transcript profiles. RNA sequencing analysis of ASCL2-deficient trophoblast cells identified both down-regulation of EVT cell-associated transcripts and up-regulation of syncytiotrophoblast-associated transcripts, indicative of dual activating and repressing functions. ASCL2 deficiency in the rat impacted placental morphogenesis, resulting in junctional zone dysgenesis and failed intrauterine trophoblast cell invasion. ASCL2 acts as a critical and conserved regulator of invasive trophoblast cell lineage development and a modulator of the syncytiotrophoblast lineage.
| S-EPMC7958375 | biostudies-literature
Project description:Natural killer (NK) cells are recruited into the uterine stroma during establishment of the hemochorial placenta and are proposed regulators of uterine spiral artery remodeling. Failures in uterine spiral artery remodeling are linked to diseases of pregnancy. This prompted an investigation of the involvement of NK cells in placentation. NK cell depletion decreased the delivery of proangiogenic factors and delayed uterine spiral artery development, leading to decreased oxygen tension at the placentation site, stabilized hypoxia-inducible factor 1A protein, and redirected trophoblast differentiation to an invasive phenotype. Trophoblast cells replaced the endothelium of uterine spiral arteries extending the depth of the placental vascular bed and accelerating vessel remodeling. Hypoxia-regulated trophoblast lineage decisions, including expansion of invasive trophoblast, could be reproduced in vitro by using rat trophoblast stem cells and were dependent on hypoxia-inducible factor signaling. We conclude that NK cells guide hemochorial placentation through controlling a hypoxia-sensitive adaptive reflex regulating trophoblast lineage decisions.
| S-EPMC3182743 | biostudies-literature
Project description:Hemochorial placentation involves the differentiation of invasive trophoblast cells, specialized cells that possess the capacity to exit the placenta and invade into the uterus where they restructure the vasculature. Invasive trophoblast cells arise from a well-defined compartment within the placenta, referred to as the junctional zone in rat and the extravillous trophoblast cell column in human. In this study, we investigated roles for AKT1, a serine/threonine kinase, in placental development using a genome-edited/loss-of-function rat model. Disruption of AKT1 resulted in placental, fetal and postnatal growth restriction. Forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate, was abundantly expressed in the junctional zone and in invasive trophoblast cells of the rat placentation site. Foxo4 gene disruption using genome editing resulted in placentomegaly, including an enlarged junctional zone. AKT1 and FOXO4 regulate the expression of many of the same transcripts expressed by trophoblast cells, but in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network that reciprocally controls critical indices of hemochorial placenta development.
| S-EPMC10110493 | biostudies-literature
Project description:Functions of Ascl2 in colonic stem cell maintenance and regeneration. We used RNA-sequencing to profile gene expression in regenerating crypt cells and Ascl2-deficient colonic stem cells, and ASCL2 ChIP-seq to identify transcriptional target genes.
2020-01-17 | GSE130822 | GEO
Project description:Wnt signals control three functions of intestinal crypts: maintenance of Lgr5 stem cells, proliferation of transit-amplifying daughters and formation of Paneth cells. Here, we study how the Wnt effector β-catenin/Tcf4 cooperates with the Wnt-activated transcription factor Ascl2 to control a stem cell transcription program. DNA elements that are co-occupied and synergistically regulated by Ascl2 and Tcf4 specifically map to stem cell genes. In vitro, Tcf4-/- mini-guts are rescued by Ascl2 expression, while Ascl2-/- organoids are rescued by Wnt signaling. A direct auto-activatory loop leads to an on/off expression pattern of Ascl2 with a threshold that depends on the previous state. Wnt/R-spondin1 activates this loop. This mechanism interprets Wnt levels in crypts and translates this continuous signal into a discrete Ascl2 âonâ or âoffâ decision. In turn Ascl2, together with β-catenin/Tcf, activates stem cell genes. Thus, Ascl2 forms a transcriptional 'stemness switch' that is both Wnt-responsive and Wnt-dependent Examination of Tcf4, B-catenin and Ascl2 DNA occupancy in murine intestinal organoids and human colorectal cancer cell lines *** Original raw files unavailable due to loss during backup ***
2016-07-15 | E-GEOD-84456 | biostudies-arrayexpress
Project description:The small intestinal epithelium is the most rapidly self-renewing tissue of mammals. Proliferative cells are confined to crypts, while differentiated cell types predominantly occupy the villi. We recently demonstrated the existence of a long-lived pool of cycling stem cells defined by Lgr5 expression and intermingled with post-mitotic Paneth cells at crypt bottoms. We have now determined a gene signature for these so called Crypt Base Columnar (CBC) cells. One of the genes within this stem cell signature is the Wnt target Ascl2. Transgenic expression of the Ascl2 transcription factor throughout the intestinal epithelium induces crypt hyperplasia and de novo crypt formation on villi. Induced deletion of the Ascl2 gene in adult small intestine leads to disappearance of the CBC stem cells within days. The combined results from these gain- and loss-of-function experiments imply that Ascl2 controls intestinal stem cell fate. Experiment Overall Design: For the stem cell signature we used cell fractions of intestines from Lgr5-EGFP-ires-CreERT2 mice, expressing GFP under the control of the Lgr5 promoter. RNA was isolated from two FACS sorted cell populations, one expressing GFP at high levels (GFPhi) and the other expressing GFP at low levels (GFPlo). For the analysis of Ascl2 target genes RNA was isolated from intestinal epithelial cells of Ah-Cre/Ascl2floxed/floxed animals and Ah-Cre/Ascl2floxed/wt control animals 3 and 5 days post induction. Differentially labelled cRNA from GFPhi and GFPlo cells from two different sorts (each combining three different mice) were hybridised on 4X44K Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in two dye swap experiments, resulting in four individual arrays. For the Ascl2 target gene analysis we analyzed the 3 and 5 days PI experiments in two dye swap experiments, resulting in four individual arrays.
2009-03-25 | E-GEOD-14201 | biostudies-arrayexpress
Project description:The esophagus is protected from the hostile environment by a stratified epithelium, which renews rapidly. Homeostasis of this epithelium is ensured by a rare population of stem cells in the basal layer: Keratin 15+ (Krt15+) cells. However, little is known about the molecular mechanisms regulating their distinct features, namely self-renewal, potency, and epithelial regeneration. Achaete-Scute Family BHLH Transcription Factor 2 (ASCL2) is strongly upregulated in Krt15+ stem cells and is known to contribute to stem cell maintenance in other tissues. Herein, we investigated the role of ASCL2 in maintaining homeostasis under normal and stress conditions in the esophageal epithelium. ASCL2 overexpression severely dysregulated cell differentiation and cell fate. Proliferation was also reduced due potentially to a blockage in the G1 phase of the cell cycle or an induction of quiescence. Mass spectrometry analysis confirmed alterations in several proteins associated with differentiation and cell cycle. In addition, overexpression of ASCL2 enhanced resistance to radiation and chemotherapeutic drugs. Overall, these results denoted the role of ASCL2 as a key regulator of the proliferation-differentiation equilibrium in the esophageal epithelium.
2024-05-24 | PXD039477 | Pride
Project description:Achaete scute-like 2 (Ascl2), a basic helix-loop-helix (bHLH) transcription factor, controls the fate of intestinal stem cells. However, the role of Ascl2 in colon cancer progenitor cells remains unknown. The cell lines HT-29 (47.5-95% of CD133+ population) and LS174T (0.45% of CD133+ population) were chosen for functional evaluation of Ascl2 in colon cancer progenitor cells after gene knockdown by RNA interference. The microRNA (miRNA) microarrays identified 26 two-fold up-regulated miRNAs and 58 two-fold down-regulated miRNAs in shRNA-Ascl2/HT-29 cells and 178 two-fold up-regulated miRNAs and 172 two-fold down-regulated miRNAs in shRNA-Ascl2/LS174T cells. Two-condition experiment: shRNA-Ascl2/HT-29 cells vs. shRNA-Ctr/HT-29 cells, and shRNA-Ascl2/LS174T cells vs. shRNA-Ctr/LS174T cells. Biological replicates: 1 HT-29 cells stably transfected with shRNA-Ascl2/EGFP, 1 LS174T cells stably transfected with shRNA-Ascl2/EGFP, 1 HT-29 cells stably transfected with shRNA-Control/EGFP, and 1 LS174T cells stably transfected with shRNA-Control/EGFP, independently grown and harvested. One replicate per array.
2012-01-07 | E-GEOD-34926 | biostudies-arrayexpress
Project description:Wnt signals control three functions of intestinal crypts: maintenance of Lgr5 stem cells, proliferation of transit-amplifying daughters and formation of Paneth cells. Here, we study how the Wnt effector β-catenin/Tcf4 cooperates with the Wnt-activated transcription factor Ascl2 to control a stem cell transcription program. DNA elements that are co-occupied and synergistically regulated by Ascl2 and Tcf4 specifically map to stem cell genes. In vitro, Tcf4-/- mini-guts are rescued by Ascl2 expression, while Ascl2-/- organoids are rescued by Wnt signaling. A direct auto-activatory loop leads to an on/off expression pattern of Ascl2 with a threshold that depends on the previous state. Wnt/R-spondin1 activates this loop. This mechanism interprets Wnt levels in crypts and translates this continuous signal into a discrete Ascl2 “on” or “off” decision. In turn Ascl2, together with β-catenin/Tcf, activates stem cell genes. Thus, Ascl2 forms a transcriptional 'stemness switch' that is both Wnt-responsive and Wnt-dependent.
2014-12-31 | GSE57053 | GEO