Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA957617 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR24224035_1.fastq.gz | Fastqsanger.gz | |||
| SRR24224035_2.fastq.gz | Fastqsanger.gz | |||
| SRR24224036_1.fastq.gz | Fastqsanger.gz | |||
| SRR24224036_2.fastq.gz | Fastqsanger.gz | |||
| SRR24224037_1.fastq.gz | Fastqsanger.gz |
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Project description:We identified cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in CD using transcriptome sequencing. Thus,we elucidated the function and mechanisms of PCDH20 in gut homeostasis, barrier integrity, and CD development.
2023-06-14 | GSE230113 | GEO
Project description:BackgroundIntestinal barrier dysfunction plays a central role in the pathological onset of Crohn's disease. We identify the cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in Crohn's disease. Here we describe the function of PCDH20 and its mechanisms in gut homeostasis, barrier integrity, and Crohn's disease development.ResultsPCDH20 mRNA and protein expression is significantly downregulated in the colonic epithelium of Crohn's disease patients and mice with induced colitis compared with controls. In mice, intestinal-specific Pcdh20 knockout causes defects in enterocyte proliferation and differentiation, while causing morphological abnormalities. Specifically, the deletion disrupts barrier integrity by unzipping adherens junctions via β-catenin regulation and p120-catenin phosphorylation, thus aggravating colitis in DSS- and TNBS-induced colitis mouse models. Furthermore, we identify activating transcription factor 6 (ATF6), a key chaperone of endoplasmic reticulum stress, as a functional downstream effector of PCDH20. By administering a selective ATF6 activator, the impairment of intestinal barrier integrity and dysregulation of CHOP/β-catenin/p-p120-catenin pathway was reversed in Pcdh20-ablated mice with colitis and PCDH20-deficient colonic cell lines.ConclusionsPCDH20 is an essential factor in maintaining intestinal epithelial homeostasis and barrier integrity. Specifically, PCDH20 helps to protect against colitis by tightening adherens junctions through the ATF6/CHOP/β-catenin/p-p120-catenin axis.
| S-EPMC10320870 | biostudies-literature
Project description:ATF6 encodes a transcription factor that is activated during the Unfolded Protein Response to protect cells from ER stress. Loss of ATF6α and its paralog ATF6β, results in embryonic lethality, notochord dysgenesis, and in people, loss of ATF6α specifically, results in malformed neuroretina and congenital vision loss. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated the function of ATF6 in development using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a recently identified small molecule ATF6 agonist, and we inhibited ATF6 using iPSCs from patients harboring ATF6 mutations. We discovered that ATF6 suppresses pluripotency, enhances differentiation, and surprisingly, guides stem cells toward mesodermal cell fates. Our findings reveal a novel role for ATF6 during differentiation and identify a new strategy to robustly create mesodermal tissues through modulation of the ATF6 arm of the UPR.
2017-11-14 | GSE106847 | GEO
Project description:We recently found that the endoplasmic reticulum (ER) stress response (ERSR) is activated in surviving cardiac myocytes in a mouse model of in vivo myocardial infarction. ATF6 is an ER stress-activated transcription factor that induces ERSR genes, some of which encode proteins that may protect against ischemic damage. However, few ERSR genes have been identified in the heart, and there have been no gene expression profiling studies of ATF6-inducible genes, in vivo. We previously generated transgenic (TG) mice that express tamoxifen-activated ATF6, ATF6-MER, in the heart; ATF6-MER conferred tamoxifen-dependent ATF6 activation and protection from ischemic damage. To understand of the mechanism of ATF6-mediated cardioprotection, gene expression profiling of ATF6-MER TG mouse hearts was performed. Activated ATF6 changed expression levels of 1,162 genes in the heart; of the 775 ATF6-inducible genes, only 23 are known ERSR genes. One of the genes not expected to be induced by ATF6 is modulatory calcinuerin-interacting protein-1 (MCIP1). MCIP1 is induced in a calcineurin/NFAT-dependent manner during myocardial hypertrophy and it can feedback inhibit cardiomyocyte growth. We found that MCIP1 expression in cultured cardiomyocytes was increased by the prototypical ER stresser, tunicamycin (TM), or by simulated ischemia. Moreover, infecting cardiomyocytes with adenovirus encoding activated ATF6 induced MCIP1 expression and inhibited myocyte growth in response to the alpha 1-adrenergic agonist, phenylephrine. These results suggest that MCIP1 can be induced in the heart by ER stresses, such as ischemia. Moreover, b integrating hypertrophy and ER stress, MCIP-modulated myocyte growth may help rejuvenate nascent ER protein folding, which could contribute to protection from ischemic damage. Keywords: Gene expression analysis of the effect of activating ATF6 in the hearts of transgenic mice upon treatment with tamoxifen.
2008-03-06 | GSE8322 | GEO
Project description:We recently found that the endoplasmic reticulum (ER) stress response (ERSR) is activated in surviving cardiac myocytes in a mouse model of in vivo myocardial infarction. ATF6 is an ER stress-activated transcription factor that induces ERSR genes, some of which encode proteins that may protect against ischemic damage. However, few ERSR genes have been identified in the heart, and there have been no gene expression profiling studies of ATF6-inducible genes, in vivo. We previously generated transgenic (TG) mice that express tamoxifen-activated ATF6, ATF6-MER, in the heart; ATF6-MER conferred tamoxifen-dependent ATF6 activation and protection from ischemic damage. To understand of the mechanism of ATF6-mediated cardioprotection, gene expression profiling of ATF6-MER TG mouse hearts was performed. Activated ATF6 changed expression levels of 1,162 genes in the heart; of the 775 ATF6-inducible genes, only 23 are known ERSR genes. One of the genes not expected to be induced by ATF6 is modulatory calcinuerin-interacting protein-1 (MCIP1). MCIP1 is induced in a calcineurin/NFAT-dependent manner during myocardial hypertrophy and it can feedback inhibit cardiomyocyte growth. We found that MCIP1 expression in cultured cardiomyocytes was increased by the prototypical ER stresser, tunicamycin (TM), or by simulated ischemia. Moreover, infecting cardiomyocytes with adenovirus encoding activated ATF6 induced MCIP1 expression and inhibited myocyte growth in response to the ï¡-adrenergic agonist, phenylephrine. These results suggest that MCIP1 can be induced in the heart by ER stresses, such as ischemia. Moreover, b integrating hypertrophy and ER stress, MCIP-modulated myocyte growth may help rejuvenate nascent ER protein folding, which could contribute to protection from ischemic damage. Experiment Overall Design: 12 mice were analyzed in this study. Four treatment groups were included in this study: transgenic ATF6-MER mice treated with tamoxifen, transgenic ATF6-MER mice treated with vehicle, nontransgenic littermates treated with tamoxifen, and nontransgenic littermates treated with vehicle. Each treatment group included 3 separate biological replicate samples. Each mouse sampled was male, C57/BL6, ~30 weeks old. Each mouse was treated, then the mouse was sacrificed, the heart was extracted, and left ventricle was isolated. Total RNA was isolated from the left ventricle, and used for hybridization onto an Affymetrix mus 430 2.0 full-genome chip. Each heart was hybridized onto its own chip.
2008-04-06 | E-GEOD-8322 | biostudies-arrayexpress
Project description:Achromatopsia (ACHM) is an autosomal recessive disease that results in severe visual loss. Symptoms of ACHM include impaired visual acuity, nystagmus, and photoaversion starting from infancy; furthermore, ACHM is associated with bilateral foveal hypoplasia and absent or severely reduced cone photoreceptor function on electroretinography. Here, we performed genetic sequencing in 3 patients from 2 families with ACHM, identifying and functionally characterizing 2 mutations in the activating transcription factor 6 (ATF6) gene. We identified a homozygous deletion covering exons 8–14 of the ATF6 gene from 2 siblings from the same family. In another patient from a different family, we identified a heterozygous deletion covering exons 2 and 3 of the ATF6 gene found in trans with a previously identified ATF6 c.970C>T (p.Arg324Cys) ACHM disease allele. Recombinant ATF6 proteins bearing these exon deletions showed markedly impaired transcriptional activity by qPCR and RNA-Seq analysis compared with WT-ATF6. Finally, RNAscope revealed that ATF6 and the related ATF6B transcripts were expressed in cones as well as in all retinal layers in normal human retina. Overall, our data identify loss-of-function ATF6 disease alleles that cause human foveal disease.
2020-07-08 | GSE153978 | GEO
Project description:The Unfolded Protein Response (UPR) maintains endoplasmic reticulum (ER) homeostasis and is essential for retinal health. Activating Transcription Factor 6 (ATF6) controls a key UPR branch and upregulates genes that mitigate ER stress. Small molecule modulators of ATF6 have been characterized in cell culture models that increase or decrease the amount of the cleaved, transcriptional activator domain of ATF6 generated from the full-length precursor. However, the effects of these small molecule ATF6 modulators remains unclear in vivo, in part because of the lack of antibodies that robustly detect the cleaved, activated form of ATF6 in model organisms like mice. Here, we used targeted RNA sequencing (RNA-seq) to assess the transcriptional response to intraocular delivery of Ceapin-A7 (an ATF6 inhibitor) and AA147 (an ATF6 activator) in the mouse retina. Using this strategy, we demonstrate that Ceapin-A7 significantly suppressed ATF6 transcriptional targets, whereas AA147 induced ATF6-regulated genes in retinal tissue of the eye. We also show that neither small molecule ATF6 modulator caused retinal cell death, compromised vision, or triggered ER stress by histology, functional testing, and transcriptional analysis. These results identify a transcriptional strategy to sensitively detect and quantify Ceapin-A7 and AA147 modulation of ATF6 in vivo. These findings also identify non-toxic conditions for further in vivo evaluation of small molecule ATF6 modulators in mouse vision loss disease models linked to ER stress.
2025-08-19 | GSE289701 | GEO
Project description:Corticotomy is a clinical procedure targeting alveolar bone to activate regional acceleratory phenomenon (RAP) and promote orthodontic tooth movement (OTM). Corticotomy involves the orchestration of inflammation by macrophages, but the underlying mechanism remains unclear. Here, we identify endoplasmic reticulum (ER) stress sensor activating transcription factor 6 (ATF6) as a critical player modulating pro- and anti-inflammatory macrophage polarization. We show that macrophage-specific ATF6 deletion blocks corticotomy-induced OTM acceleration, while macrophage ATF6 overexpression exaggerates the acceleration effect. Furthermore, the proportion of pro-inflammatory macrophages is positively correlated with ATF6 expression in vitro and in vivo. By RNA-seq and CUT&Tag, we demonstrate that ATF6 interacts with Tnfα promotor and augments its transcription, thereby mediating the effect of TNF signaling pathway in pro-inflammatory macrophage polarization. In summary, ATF6 may aggravate alveolar bone remodeling during corticotomy by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerating orthodontics.
2025-04-09 | GSE246048 | GEO
Project description:Corticotomy is a clinical procedure targeting alveolar bone to activate regional acceleratory phenomenon (RAP) and promote orthodontic tooth movement (OTM). Corticotomy involves the orchestration of inflammation by macrophages, but the underlying mechanism remains unclear. Here, we identify endoplasmic reticulum (ER) stress sensor activating transcription factor 6 (ATF6) as a critical player modulating pro- and anti-inflammatory macrophage polarization. We show that macrophage-specific ATF6 deletion blocks corticotomy-induced OTM acceleration, while macrophage ATF6 overexpression exaggerates the acceleration effect. Furthermore, the proportion of pro-inflammatory macrophages is positively correlated with ATF6 expression in vitro and in vivo. By RNA-seq and CUT&Tag, we demonstrate that ATF6 interacts with Tnfα promotor and augments its transcription, thereby mediating the effect of TNF signaling pathway in pro-inflammatory macrophage polarization. In summary, ATF6 may aggravate alveolar bone remodeling during corticotomy by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerating orthodontics.
2025-04-09 | GSE245975 | GEO
Project description:We wished to determine the effects of activating the transcription factor, ATF6, on global miRNA expression. We utilized transgenic mice with a conditionally tamoxien-responsive form of ATF6 and assessed cardiac lysates from NTG and TG mice, both treated with tamoxifen and untreated, in order to identify differentially expressed miRNAs. We then focused on miRNAs of interest as well as the genes they are predicted to regulate. Four sample groups were assessed for miRNA expression: non-transgenic (NTG) mice treated with vehicle, NTG mice treated with tamoxifen, ATF6 transgenic (TG) mice treated with vehicle, and TG mice treated with tamoxifen
2012-01-02 | E-GEOD-33515 | biostudies-arrayexpress