Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcription factor Achaete scute-like 2 (Ascl2) controls intestinal stem cell fate

ABSTRACT: 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. Keywords: expression profiling

ORGANISM(S): Mus musculus

PROVIDER: GSE14201 | GEO | 2009/03/13

SECONDARY ACCESSION(S): PRJNA111203

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling of mouse intestinal cells expressing Lgr5 at high or low levels or with Ascl2 conditionally knocked out shows Ascl2 controls intestinal stem cell fate

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

Ascl2-dependent cell differentiation drives regeneration of abated intestinal stem cells

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

ASCL2 is a key regulator of the proliferation-differentiation equilibrium in the esophageal epithelium

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

Expression data from FACS-purified Lgr5-EGFP+ intestinal cells from Ubc9+/+ and Ubc9+/- mice

Project description:The Lgr5+ intestinal stem cell, Paneth and transit-amplifying cell compartment constitute the intestinal crypt which is the constant source of differentiated epithelial cells that replenish the intestinal villi ensuring organ maintenance and regeneration. The Lgr5+ crypt-based columnar (CBC) cells have been identified as the intestinal stem cells (ISCs) and, importantly, as cells-of-origin of intestinal cancer. We used microarrays to detail the global program of gene expression in normal ISCs describing a mild downregulation of the sumoylation (post-translational modification (PTM) of proteins by SUMO) imposed by the loss of one allele of the unique E2-conjugating enzyme (Ubc9) of the pathway.

2020-09-14 | GSE146106 | GEO

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Project description:The currently accepted intestinal epithelial cell organization model equates crypt base columnar (CBC) cells, marked by high levels of Lgr5 expression, with the intestinal stem cell (ISC). However, recent intestinal regeneration studies have uncovered limitations of the ‘Lgr5-CBC’ model, leading to two major views: one favoring the presence of a quiescent reserve stem cell population, the other calling for differentiated cell plasticity. To test if an alternative model may help reconcile these perspectives, we studied the hierarchical organization of crypt epithelial cells in an unbiased fashion, by combining high-resolution, single-cell profiling and lineage tracing in multiple transgenic mouse models. These show that Lgr5 is not a specific ISC marker; rather, cells located in the crypt isthmus, which include Lgr5low cells, comprise the ISCs that sustain tissue homeostasis. Following irradiation or intestinal injury, surviving ISCs and progenitors, but not differentiated cells, participate in intestinal regeneration, suggesting that neither de-differentiation nor reserve stem cell populations are drivers of intestinal regeneration. Our results provide a novel viewpoint for the intestinal crypt epithelium, in which ISCs localize to the crypt isthmus, and ISC potential is restricted to stem and progenitor cells.

2024-03-24 | GSE205229 | GEO

Single intestinal stem cells build crypt-villus structures in vitro without a cellular niche

Project description:The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of approximately six cycling Lgr5+ stem cells at the bottoms of small intestinal crypts1. We have now established long-term culture conditions under which single crypts undergo multiple crypt fission events, whilst simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5+ stem cells can also initiate these crypt-villus organoids. Tracing experiments indicate that the Lgr5+ stem cell hierarchy is maintained in organoids. We conclude that intestinal crypt-villus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche. Keywords: expression profiling

2009-04-03 | GSE14594 | GEO

Ascl2 acts as an R-spondin/Wnt responsive switch to control stemness in intestinal crypts [ChIP-seq]

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 Î²-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 Î²-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

Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells

Project description:The intestinal epithelium has a remarkably high turnover in homeostasis. It remains unresolved how turnover is orchestrated at the cellular level and how the behaviour of stem and progenitor cells ensures tissue maintenance. To address this, we combined quantitative fate mapping in three complementary mouse models with mathematical modelling and single-cell RNA sequencing. Our integrated approach generated a spatially and temporally defined model of crypt maintenance that is based on two cycling populations: crypt-based columnar (CBC) and transit amplifying (TA) cells. Validation experiments substantiated the predictions from the model revealing TA cells as the major contributor to the absorptive lineage, while balanced CBC cell fate choices controlled the numbers of cells in the secretory lineage. By unravelling these mechanisms, we gain insights into the process of tissue turnover and provide direct evidence to support the notion of CBC cells as the major driver of the intestinal epithelium replenishment.

2024-12-06 | GSE241524 | GEO

RNA-seq of crypt and villus cells from mouse small intestinal epithelium with an intestinal-epithelial specific deletion of LSD1 compared to wild type controls

Project description:To assess the role of LSD1 in mouse small intestinal epithelium, we isolated small intestinal crypts and villus from wild type (WT) (Villin-Cre -; Lsd1f/f) and intestinal-epithelial-specific knock-out (cKO) (Villin-Cre+; Lsd1f/f) mice. This experiment uses a new Cre strain with 100% deletion efficiency. RNA was directly isolated from intestinal crypt and villus, and this was used for RNAseq. Gene expression analysis of cKO derived crypt and villus provides a spatially restricted outlook on the maturation status of the intestinal epithelium in the villi and the absence of Paneth cells in the crypt.

2023-08-02 | E-MTAB-10498 | biostudies-arrayexpress

A positive regulatory loop between a Wnt-regulated non-coding RNA and ASCL2 controls intestinal stem cell fate

Project description:The canonical Wnt pathway plays a central role in stem cell maintenance, differentiation and proliferation in the intestinal epithelium. Constitutive, aberrant activity of the TCF4/β-catenin transcriptional complex is the primary transforming factor in colorectal cancer. Despite significant recent inroads, the full complement of Wnt target genes and the mechanisms of regulation remain incompletely understood. Here we identify a nuclear long non-coding RNA, termed WiNTRLINC1, as a direct target of TCF4/β-catenin in colorectal cancer cells. WiNTRLINC1 positively regulates the expression of its close neighbor ASCL2, a transcription factor that controls intestinal stem cell fate. WiNTRLINC1 interacts with TCF4/β-catenin to mediate the juxtaposition/physical contact of its own promoter with the regulatory regions of ASCL2. ASCL2, in turn, regulates WiNTRLINC1 expression. This feedforward regulatory loop controls stem cell-related gene expression and is highly amplified in colorectal cancer.

2016-06-09 | GSE69036 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data