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IκBα deficiency imposes a fetal phenotype to intestinal stem cells

ABSTRACT: The intestinal epithelium is a paradigm of adult tissue in constant regeneration that is supported by intestinal stem cells (ISCs). The mechanisms regulating ISC homeostasis after injury are poorly understood. We previously demonstrated that IκBa, not only controls NF-κB activation, but also exerts nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. We now uncover nuclear phosphorylated IκBa (P-IκBa) in the ISC compartment where it binds highly histone methylated genomic regions. Mice deficient for IκBa show aberrant distribution of H3K27me3 mark, and altered intestinal differentiation with persistence of a fetal-like ISC signature. In vitro, IκBa deficient intestinal cells produced morphologically aberrant organoids carrying a PRC2, Notch and IFN-dependent fetal-like transcriptional signature. Induction of the fetal-like phenotype by DSS treatment is associated with loss of nuclear P-IκBa in the damaged colonic epithelium and it subsequent accumulation in early CD44 positive regenerating areas. Importantly, IκBa deficient animals showed higher resistance to damage, likely due to persistent fetal-like phenotype. These results point out intestinal IκBa as chromatin sensor of inflammation in the ISC compartment.

ORGANISM(S): Mus musculus

PROVIDER: GSE130937 | GEO | 2020/02/04

REPOSITORIES: GEO

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IκBα deficiency imposes a fetal phenotype to intestinal stem cells [RNA-seq]

Project description:The intestinal epithelium is a paradigm of adult tissue in constant regeneration that is supported by intestinal stem cells (ISCs). The mechanisms regulating ISC homeostasis after injury are poorly understood. We previously demonstrated that IκBa, not only controls NF-κB activation, but also exerts nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. We now uncover nuclear phosphorylated IκBa (P-IκBa) in the ISC compartment where it binds highly histone methylated genomic regions. Mice deficient for IκBa show aberrant distribution of H3K27me3 mark, and altered intestinal differentiation with persistence of a fetal-like ISC signature. In vitro, IκBa deficient intestinal cells produced morphologically aberrant organoids carrying a PRC2, Notch and IFN-dependent fetal-like transcriptional signature. Induction of the fetal-like phenotype by DSS treatment is associated with loss of nuclear P-IκBa in the damaged colonic epithelium and it subsequent accumulation in early CD44 positive regenerating areas. Importantly, IκBa deficient animals showed higher resistance to damage, likely due to persistent fetal-like phenotype. These results point out intestinal IκBa as chromatin sensor of inflammation in the ISC compartment.

2020-02-04 | GSE131186 | GEO

IκBα deficiency imposes a fetal phenotype to intestinal stem cells [ChIP-seq]

2020-02-04 | GSE131185 | GEO

Sox4 regulates proliferation, differentiation, and DNA methylation patterns in the intestinal epithelium

Project description:Intestinal stem cells (ISCs) are responsible for maintaining the physiological function of the intestinal epithelium through the production of differentiated absorptive and secretory cellular lineages. In addition to producing specialized functional cells, ISCs must also drive constant proliferation in order to maintain the especially high rate of cellular turnover in the intestinal epithelium, which undergoes near total renewal every 5-7 days. Understanding the transcriptional mechanisms that control how ISCs and transit-amplifying progenitors (TAs) balance differentiation and proliferation in the intestine may provide valuable insight into common pathologies, such as inflammatory bowel disease and cancer. Here, we show that the Sry¬¬-box containing transcription factor, Sox4, is involved in the regulation of proliferation in the ISC/TA zone, the expression of ISC-associated genes, and the differentiation of enteroendocrine (EE) cells. Interestingly, we also observed a significant reduction in the expression of the methylcytosine dioxygenase, Tet1, in Sox4-deficient intestines. We find that Tet1, which initiates derepression of target genes via DNA demethylation, is specifically upregulated in ISC populations in wild-type animals. Additionally, Sox4-deficient intestines showed a significant reduction in levels of 5-hydroxymethylcytosine, the catalytic byproduct of TET protein activity, in the ISC/TA zone. Together, our data demonstrate that Sox4 regulates differentiation and proliferation in the intestinal epithelium, and suggests that it may influence these processes through induction of Tet1 and subsequent derepression of target genes through epigenetic mechanisms.

2014-12-31 | GSE52675 | GEO

Ribosome impairment regulates intestinal stem cell identity via ZAKa activation.

Project description:The small intestine is a rapidly proliferating organ that is maintained by a small population of Lgr5-expressing intestinal stem cells (ISCs). However, several Lgr5-negative ISC populations have been identified, and this remarkable plasticity allows the intestine to rapidly respond to both the local environment and to damage. The mediators of such plasticity are still largely unknown. Using intestinal organoids and mouse models, we show that upon ribosome impairment (driven by Rptor deletion, amino acid starvation, or low dose cyclohexamide treatment) ISCs gain an Lgr5-negative, fetal-like identity. This is accompanied by a rewiring of metabolism. Our findings suggest that the ribosome can act as a sensor of nutrient availability, allowing ISCs to respond to the local nutrient environment. Mechanistically, we show that this phenotype requires the activation of ZAKɑ, which in turn activates YAP, via SRC. Together, our data reveals a central role for ribosome dynamics in intestinal stem cells, and identify the activation of ZAKɑ as a critical mediator of stem cell identity.

2022-06-13 | PXD033122 | Pride

Intestinal subepithelial myofibroblasts support the growth of intestinal epithelial stem cells

Project description:Intestinal epithelial stem cells (ISCs) are the focus of recent intense study. Current in vitro models rely on supplementation with the Wnt agonist R-spondin1 to support robust growth, ISC self-renewal, and differentiation. Intestinal subepithelial myofibroblasts (ISEMFs) are important supportive cells within the ISC niche. We hypothesized that co-culture with ISEMF enhances the growth of ISCs in vitro and allows for their successful in vivo implantation and engraftment. ISC-containing small intestinal crypts, FACS-sorted single ISCs, and ISEMFs were procured from C57BL/6 mice. Crypts and single ISCs were grown in vitro into enteroids, in the presence or absence of ISEMFs. ISEMFs enhanced the growth of intestinal epithelium in vitro in a proximity-dependent fashion, with co-cultures giving rise to larger enteroids than monocultures. Co-culture of ISCs with supportive ISEMFs relinquished the requirement of exogenous R-spondin1 to sustain long-term growth and differentiation of ISCs. Mono- and co-cultures were implanted subcutaneously in syngeneic mice. Co-culture with ISEMFs proved necessary for successful in vivo engraftment and proliferation of enteroids; implants without ISEMFs did not survive. ISEMF whole transcriptome sequencing and qPCR demonstrated high expression of specific R-spondins, well-described Wnt agonists that supports ISC growth. Specific non-supportive ISEMF populations had reduced expression of R-spondins. The addition of ISEMFs in intestinal epithelial culture therefore recapitulates a critical element of the intestinal stem cell niche and allows for its experimental interrogation and biodesign-driven manipulation. Two samples of intestinal subepithelial myofibroblasts were used in this study.

2013-12-20 | E-GEOD-52402 | biostudies-arrayexpress

Analysis of transcriptomes in intestinal stem cells in response to Interferon gamma

Project description:There is limited understanding of how immune-mediated damage impacts intestinal stem cells (ISCs). We found that stem cell compartment injury is a shared feature of both alloreactive and autoreactive intestinal immunopathology, reducing ISCs and impairing their recovery in T-cell-mediated injury models. Modeling with ex vivo epithelial cultures indicated ISC depletion and impaired human as well as murine organoid survival upon co-culture with activated T cells, and screening of effector pathways identified Interferon-γ (IFNγ) as a principal mediator of ISC compartment damage. Flow cytometry analysis confirmed expression of IFNγ receptor on ISCs. To investigate if the receptor was functional, we performed transcriptome analysis of ISCs treated with IFNγ. In brief, mRNA profiles of sorted Lgr5-high cells treated with/without IFNγ were generated by deep sequencing, in triplicate, using the TruSeq SBS Kit V4 (Illumina). RNA profiles confirmed a robust IFNγ transcriptional signature in the stem cells, as several IFNγ-related genes were upregulated shortly after exposure, indicating direct activity of IFNγ in ISCs. Epithelial cultures with IFNγ-receptor-deficient ISCs and purified stem cell colonies also indicated direct targeting of the ISCs. This study showed that dysregulated T cell activation and Interferon-γ production are potent mediators of ISC injury.

2019-11-02 | GSE139813 | GEO

Gut-liver axis calibrates intestinal stem cell fitness via PEDF

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2023-03-03 | MSV000091409 | MassIVE

In vitro grown organoids treated with IFNγ mimicking in vivo intestinal crypts cells aging

Project description:Aging-related intestinal dysfunctions include loss of barrier integrity, altered stress responses, nutrient malabsorption, and cancer formation. Influence of aging on intestinal stem cell (ISC) and their niches can explain underlying causes for perturbation in ISC function during aging. However, molecular mechanisms for such decrease in functionality of ISCs during aging remain largely undetermined. Using different transcriptome-wide approaches including single-cell RNA-seq from intestinal crypt cells and immune cells of lamina propria, we characterized age-specific transcriptional programs in the intestinal epithelium. We found that aged ISCs strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes leading to a compromised homeostasis of the intestinal epithelium. Mechanistically, increase of interferon gamma (IFNgamma) release by cytotoxic CD4 T cells and innate lymphoid type 2 cells (ILC2) in lamina propria of aged intestine lead to induction of Stat1 in ISCs that trigger MHC class II expression and prime them towards a secretory fate. Altogether these findings, clarify the cross talk between immune cells and ISC in aged intestine and identified the IFNgamma-Stat1-MHCII axis as the key gene network driving intestinal inflammaging phenotype and loss of tissue homeostasis. Our data provide basic and complementary knowledge for the development of therapeutic intervention for aging-related intestinal dysfunction and diseases.

2023-09-05 | GSE174297 | GEO

Gene expression in intestinal stem cells

Project description:Genetic Manipulation to increase number of ISC (intestinal stem cells) and gene expression profiling to identify ISC regulators Fly midguts were dissected from wild type and transgenic animals

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