Loss of ARID1A induces a stemness gene ALDH1A1 expression with histone acetylation in the malignant subtype of cholangiocarcinoma
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PROVIDER: PRJNA525761 | ENA |
REPOSITORIES: ENA
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Project description:Genomic analyses have recently discovered the malignant subtype of human intrahepatic cholangiocarcinoma (ICC) characterized by frequent mutations of chromatin remodeling gene ARID1A, however, the biological and molecular functions still remain obscure. We here examined the clinical and biological significances of ARID1A deficiency in human ICC. Immunohistochemical analysis demonstrated that loss of ARID1A was an independent prognostic factor for overall survival of ICC patients (P = 0.023). We established ARID1A-knockout (KO) cells by using the CRISPR/Cas9 system from two human cholangiocarcinoma cell lines. ARID1A-KO cells significantly enhanced migration, invasion, and sphere formation activity. Microarray analysis revealed that ALDH1A1, a stemness gene, was the most significantly elevated genes in ARID1A-KO cells. In addition, ALDH enzymatic activity as a hallmark of cancer stem cells was markedly high in the KO cells. ARID1A and histone deacetylase 1 directly recruited to the ALDH1A1 promoter region in cholangiocarcinoma cells with undetectable ALDH1A expression by chromatin immunoprecipitation assay. The histone H3K27 acetylation level at the ALDH1A1 promoter region was increased in cells when ARID1A was disrupted (P < 0.01). Clinically, inverse correlation between ARID1A and ALDH1A expression was also detected in primary ICC (P = 0.018), and ARID1A-negative and ALDH1A1-positve ICCs showed worse prognosis than only ARID1A-negative cases (P = 0.002). In conclusion, ARID1A may function as a tumor suppressor in ICC through transcriptional down-regulation of ALDH1A1 expression with decreasing histone H3K27 acetylation. Our studies provide the basis for the development of new epigenetic approaches to ARID1A-negative ICC.
2021-03-01 | GSE127897 | GEO
Project description:Endometrial stem cells and their regenerative properties are implicated in the pathogenesis of endometriosis. Using single-cell RNA sequencing of the adult mouse endometrial epithelium, we identified a sub-population of aldehyde dehydrogenase 1a1+ (Aldh1a1+) stem-like cells that co-expresses stemness genes (Lgr5, Axin2) and lack proliferative markers (Top2a, Mki67). Using an Aldh1a1cre/ERT2;ROSA26tdTomato reporter mouse, we found that Aldh1a1+ cells give rise to long-lived endometrial cells and contribute to post-partum endometrial repair. Selective ablation of ALDH1A1+ cells with diphtheria toxin (DT) in Aldh1a1cre/ERT2; ROSA26-DTRflox/flox mice decreased glands and FOXA2 expression in vivo. Mouse and human ALDHHI endometrial cells had higher organoid formation capacity and stem-like gene signatures than ALDHLO cells. Ectopic lesion-derived organoids showed higher ALDH activity than patient-matched eutopic cells and displayed enriched pro-inflammatory, stemness, and ciliated cell transcriptomes. Here we provide evidence that ALDH1A1+ cells display progenitor/stem cell characteristics in the endometrium and contribute to the pathology of endometriosis.
2026-07-01 | GSE294256 | GEO
Project description:Endometrial stem cells and their regenerative properties are implicated in the pathogenesis of endometriosis. Using single-cell RNA sequencing of the adult mouse endometrial epithelium, we identified a sub-population of aldehyde dehydrogenase 1a1+ (Aldh1a1+) stem-like cells that co-expresses stemness genes (Lgr5, Axin2) and lack proliferative markers (Top2a, Mki67). Using an Aldh1a1cre/ERT2;ROSA26tdTomato reporter mouse, we found that Aldh1a1+ cells give rise to long-lived endometrial cells and contribute to post-partum endometrial repair. Selective ablation of ALDH1A1+ cells with diphtheria toxin (DT) in Aldh1a1cre/ERT2; ROSA26-DTRflox/flox mice decreased glands and FOXA2 expression in vivo. Mouse and human ALDHHI endometrial cells had higher organoid formation capacity and stem-like gene signatures than ALDHLO cells. Ectopic lesion-derived organoids showed higher ALDH activity than patient-matched eutopic cells and displayed enriched pro-inflammatory, stemness, and ciliated cell transcriptomes. Here we provide evidence that ALDH1A1+ cells display progenitor/stem cell characteristics in the endometrium and contribute to the pathology of endometriosis.
2026-07-01 | GSE294255 | GEO
Project description:Endometrial stem cells and their regenerative properties are implicated in the pathogenesis of endometriosis. Using single-cell RNA sequencing of the adult mouse endometrial epithelium, we identified a sub-population of aldehyde dehydrogenase 1a1+ (Aldh1a1+) stem-like cells that co-expresses stemness genes (Lgr5, Axin2) and lack proliferative markers (Top2a, Mki67). Using an Aldh1a1cre/ERT2;ROSA26tdTomato reporter mouse, we found that Aldh1a1+ cells give rise to long-lived endometrial cells and contribute to post-partum endometrial repair. Selective ablation of ALDH1A1+ cells with diphtheria toxin (DT) in Aldh1a1cre/ERT2; ROSA26-DTRflox/flox mice decreased glands and FOXA2 expression in vivo. Mouse and human ALDHHI endometrial cells had higher organoid formation capacity and stem-like gene signatures than ALDHLO cells. Ectopic lesion-derived organoids showed higher ALDH activity than patient-matched eutopic cells and displayed enriched pro-inflammatory, stemness, and ciliated cell transcriptomes. Here we provide evidence that ALDH1A1+ cells display progenitor/stem cell characteristics in the endometrium and contribute to the pathology of endometriosis.
2026-07-01 | GSE294257 | GEO
Project description:Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the US. Ovarian cancer stem cells (OCSCs) have been shown to drive chemoresistance and tumor progression but the mechanism remains incompletely understood. Aldehyde Dehydrogenase 1A1 (ALDH1A1) is a robust marker for cancer stem cells in ovarian and other cancers. We demonstrate that ALDH1A1 inhibition suppresses stemness, chemoresistance and senescence in ovarian cancer.
2022-08-03 | GSE200641 | GEO
Project description:ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. In this study, we identified the anti-senescence effect of ARID1A deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in the mouse model. Interestingly, we found that ARID1A deficiency activates the transcription of Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), which play essential roles in attenuating the senescence by significantly reducing reactive oxygen species (ROS) induced by oncogenic KRAS. Our findings further suggest that ALDH could be considered as a potential adjuvant target for prevention and treatment of pancreatic cancer.
2021-06-06 | GSE160440 | GEO
Project description:ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. In this study, we identified the anti-senescence effect of ARID1A deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in the mouse model. Interestingly, we found that ARID1A deficiency activates the transcription of Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), which play essential roles in attenuating the senescence by significantly reducing reactive oxygen species (ROS) induced by oncogenic KRAS. Our findings further suggest that ALDH could be considered as a potential adjuvant target for prevention and treatment of pancreatic cancer.
2021-06-06 | GSE160442 | GEO
Project description:ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. In this study, we identified the anti-senescence effect of ARID1A deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in the mouse model. Interestingly, we found that ARID1A deficiency activates the transcription of Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), which play essential roles in attenuating the senescence by significantly reducing reactive oxygen species (ROS) induced by oncogenic KRAS. Our findings further suggest that ALDH could be considered as a potential adjuvant target for prevention and treatment of pancreatic cancer.
2021-06-06 | GSE160443 | GEO
Project description:The goal of this study was to identify preadipocyte signature genes that are dependent in aldehyde dehydrogenase 1a1 (Aldh1a1) by comparison genomes of the immortalized wild type and Aldh1a1-/- preadipocytes. Gene expression was measured using theAffymetrix GeneChip Mouse Gene ST 2.0 arrays. Murine wild type (n=3, control) and Aldh1a1-/- preadipocytes (n=3) were cultured in standard DMEM medium containing 10% of calf serum. mRNA was isolated by RNeasy (Qiagen, Valencia, CA). RNA integrity was interrogated using the Agilent 2100 Bioanalyzer (Agilent Technologies). A 100ng aliquot of total RNA was linearly amplified. Then, 5.5ug of cDNA was labeled and fragmented using the GeneChip WT PLUS reagent kit (Affymetrix, Santa Clara, CA) following the manufacturer's instructions. Labeled cDNA targets were hybridized to Affymetrix GeneChip Mouse Gene ST 2.0 arrays for 16 h at 45 °C rotating at 60rpm. The arrays were washed and stained using the Fluidics Station 450 and scanned using the GeneChip Scanner 3000. Signal intensities were quantified by Affymetrix Expression Console version 1.3.1. Background correction and quantile normalization was performed to adjust technical bias, and probe-set expression levels were calculated by RMA method. After filtering above noise cutoff, there are 9,528 probe-sets that were tested by linear model. A variance smoothing method with fully moderated t-statistic was employed for this study and was adjusted by controlling the mean number of false positives. With a combined cutoff of 2-fold change and p-value of 0.0001 (controlling 1 false positive over all probe-sets), we declared 500 probe-sets as differential gene expression between Aldh1a1-/- and WT preadipocytes.
2016-07-03 | E-GEOD-69573 | biostudies-arrayexpress
Project description:To explore potential impact of Aldh1a1 deficiency in the retinoic acid signaling in the lung, gene expression levels were compared between wildtype and Aldh1a1 deficient lung tissues. The expression levels of retinoic acid responsive genes were very similar between wildtype and Aldh1a1 deficient lungs, suggesting that Aldh1a1 deficiency has minimal impact on retinoic acid signaling.
2024-09-16 | GSE267105 | GEO