Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity
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PROVIDER: PRJNA1013187 | ENA |
REPOSITORIES: ENA
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Project description:HuR stimulates the activity of intestinal stem cells by enhancing Paneth cell function via activation of mitochondrial metabolism, thus promoting renewal of the intestinal mucosa
2023-09-08 | GSE242410 | GEO
Project description:Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity. Targeted deletion of HuR in mice disrupted PC gene expression profiles, reduced PC-derived niche factors, and impaired ISC function, leading to inhibited renewal of the intestinal epithelium. Human intestinal mucosa from patients with critical surgical disorders exhibited decreased levels of tissue HuR and PC/ISC niche dysfunction, along with disrupted mucosal growth. HuR deletion led to mitochondrial impairment by decreasing the levels of several mitochondrial-associated proteins including prohibitin 1 (PHB1) in the intestinal epithelium, whereas HuR enhanced PHB1 expression by preventing microRNA-195 binding to the Phb1 mRNA. These results indicate that HuR is essential for maintaining the integrity of the PC/ISC niche and highlight a novel role for a defective PC/ISC niche in the pathogenesis of intestinal mucosa atrophy.
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Project description:Paneth cells are the primary, and possibly the sole, source of lysozyme in the intestinal lumen. Mice lacking the Paneth cell lysozyme gene, Lyz1, had diminished NLR signaling and basal inflammation, and were further protected from experimental colitis. Protection depended on an enhanced goblet and tuft cell program that was driven by IL13-IL4Ra-Stat6 signaling and required an expansion of lysozyme-sensitive mucolytic bacteria. Forced ectopic lysozyme production in colonic epithelium suppressed these bacteria and exacerbated colitis. Single cell RNA-seq of Lyz1 KO lamina propria revealed an activated ILC2 profile towards cytokine production. One lysozymesensitive species, Ruminococcus gnavus , when processed by lysozyme, induced a pro-inflammatory response, while non-processed R. gnavus stimulated IL13 production in lymphocytes. Consistent with a role of lysozyme for cell-wall processing in the inflammatory response, Lyz1 KO microbiota was anti-colitogenic in lysozymedeficient hosts but colitogenic in lysozyme-sufficient hosts. Thus, Paneth cell lysozyme regulates inflammatory tone by modulating mucosal response to specific bacterial groups.
2020-08-19 | GSE151151 | GEO
Project description:Paneth cell-derived intestinal luminal lysozyme shapes mucolytic microbiota and controls mucosal inflammatory tone
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Project description:The single cell level Paneth cell transcriptome under gnotobiotic condition has not been resolved. How gut microbiome modulates Paneth cell transcriptome at single cell level in germ-free mice was not known. We used a flow cytometry method to isolate highly pure ileal Paneth cells from germ free (GF) Paneth cell reporter mice (Lyz1-3'UTR-IRES-CreER) and from exGF Paneth cell reporter mice that were transplanted with wild type C57B/l6 mouse gut microbiota (exGF+B6M). These isolated Paneth cells were subjected to single cell RNA sequencing by 10xGenomics.
2023-09-01 | GSE237328 | GEO
Project description:An indepth analysis of Paneth cell transcriptome at single cell level has not been available. Existing intestinal epithelial cell scRNA dataset contain many cell types, where Paneth cells represent a small portion. We used a flow cytometry based approach to enrich and isolate relatively pure Panethc cells from a newly developed Paneth cell reporter mouse line (Lyz1-3'UTR-IRES-CreER; Rosa26R-tdTomato). Single cell RNA sequencing was performed on purified duodenal and ileal Paneth cells of mice housed under specific pathogen free condition.
2023-09-01 | GSE237327 | GEO
Project description:Paneth cells consist of heterogeous phenotypes. How Paneth cells respond to infection by invasive pathogenic bacteria at single cell level remains uncharacterized. We used a flow cytometry based method to isolate Paneth cells from uninfected and Salmonella-infected Paneth cell reporter mice (Lyz1-3'UTR-IRES-CreER; Rosa26R-tdTomato). These highly pure Paneth cell populations were used for single cell RNA sequencing analysis.
2023-09-01 | GSE237326 | GEO
Project description:Long non-coding RNAs (lncRNAs) regulate vital biological processes, including cell proliferation, differentiation and development. A subclass of lncRNAs is synthesized from microRNA host genes (MIRHGs) due to pre-miRNA processing, and is categorized as miRNA-host gene lncRNAs (lnc-miRHGs). Presently, it is not clear whether lnc-miRHG perform additional functions. We demonstrate a miRNA-independent role for a nuclear-enriched lnc-miRHG in cell cycle progression. MIR100HG produces spliced and stable lncRNAs (lnc-MIR100HG) that display elevated levels during the G1 phase of the cell cycle. Depletion of lnc-MIR100HG in human cells results in aberrant cell cycle progression with out altering the levels of miRNA encoded within MIR100HG. Notably, lnc-MIR100HG interacts with the HuR/Elav as well as with several of HuR-target mRNAs. Further, lnc-MIR100HG-depleted cells show reduced interaction between HuR and its target mRNAs, indicating that lnc-MIR100HG facilitates interaction between HuR and target mRNAs. Our studies have unearthed novel roles played by miRHG-encoded lncRNAs in regulating RNA binding protein activity, thereby underscoring the importance of determining the function of several hundreds of miRHG lncRNAs that are present in human genome.
2018-07-23 | GSE108280 | GEO
Project description:BACKGROUND & AIMS:Paneth cells secrete antimicrobial proteins including lysozyme via secretory autophagy as part of the mucosal protective response. The ELAV like RNA-binding protein 1 (ELAVL1, also called HuR) regulates stability and translation of messenger RNAs (mRNAs) and many aspects of mucosal physiology. We studied the posttranscriptional mechanisms by which HuR regulates Paneth cell function. METHODS:Intestinal mucosal tissues were collected from mice with intestinal epithelium (IE)-specific disruption of HuR (IE-HuR-/-), HuRfl/fl-Cre- mice (controls), and patients with inflammatory bowel diseases and analyzed by histology and immunohistochemistry. Paneth cell functions were determined by lysozyme-immunostaining assays. We isolated primary enterocytes from IE-HuR-/- and control mice and derived intestinal organoids. HuR and the chaperone CNPY3 were overexpressed from transgenes in intestinal epithelial cells (IECs) or knocked down with small interfering RNAs. We performed RNA pulldown assays to investigate interactions between HuR and its target mRNAs. RESULTS:Intestinal tissues from IE-HuR-/- mice had reduced numbers of Paneth cells, and Paneth cells had fewer lysozyme granules per cell, compared with tissues from control mice, but there were no effects on Goblet cells or enterocytes. Intestinal mucosa from patients with inflammatory bowel diseases had reduced levels of HuR and fewer Paneth cells. IE-HuR-/- mice did not have the apical distribution of TLR2 in the intestinal mucosa as observed in control mice. IECs from IE-HuR-/- mice expressed lower levels of CNPY3. Intestinal organoids from IE-HuR-/- mice were smaller and contained fewer buds compared with those generated from controls, and had fewer lysozyme-positive cells. In IECs, knockdown of HuR decreased levels of the autophagy proteins LC3-I and LC3-II, compared with control cells, and prevented rapamycin-induced autophagy. We found HuR to interact directly with the Cnpy3 mRNA coding region and increase levels of CNPY3 by increasing the stability and translation of Cnpy3 mRNA. CNPY3 bound TLR2, and cells with knockdown of CNPY3 or HuR lost membrane localization of TLR2, but increased cytoplasmic levels of TLR2. CONCLUSIONS:In studies of mice, IECs, and human tissues, we found HuR to increase expression of CNPY3 at the posttranscriptional level. CNPY3 is required for membrane localization of TLR2 and Paneth cell function.
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