KMT2A-driven cyclin D2 upregulation and chronic inflammation as potential drivers of sporadic parathyroid adenoma pathogenesis
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ABSTRACT:
PROVIDER: PRJNA788456 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17216000_1.fastq.gz | Fastqsanger.gz | |||
| SRR17216000_2.fastq.gz | Fastqsanger.gz | |||
| SRR17216001_1.fastq.gz | Fastqsanger.gz | |||
| SRR17216001_2.fastq.gz | Fastqsanger.gz | |||
| SRR17216002_1.fastq.gz | Fastqsanger.gz |
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Project description:Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, but the mechanisms involved in its pathogenesis remain incompletely understood. Here we present a single-cell transcriptomic atlas detailing the cellular differences between human PA and normal parathyroid gland (PG) tissues and delineating the transcriptome of individual cell types. We show that there is a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells (PGCs), with transcriptional upregulation of cyclin D2 driven by the transcriptional coactivator, histone-lysine N-methyltransferase 2A (KMT2A) through the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3) potentially involved in promoting PAC proliferation. Moreover, we demonstrate that PA tissues are heavily infiltrated with myeloid cells, and that fibroblasts, endothelial cells (ECs), as well as macrophages in the PA microenvironment are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. Collectively, these results provide new insights into the etiology of PA, where the pathogenesis likely involves the net contribution of the dysregulated KMT2A-STAT3/GATA3-cyclin D2 axis in PACs and the chronic inflammation of the microenvironment. These findings provide practical implications for the treatment of PA through KMT2A targeting and anti-inflammation therapies.
2024-05-01 | GSE190773 | GEO
Project description:Transcriptional profiling of genes expressed in normal parathyroid glands (Normal) and adenomatous parathyroid glands from patients with primary hyperparathyroidism (PHPT). Stratagen Human Refernece RNA, pooled from 10 human cell lines, was used to identify genes, which are specifically expressed or suppressed in parathyroid tissue. Comparison between normal and tumor parathyroids shows genes that might be involved in hyperproliferation and PTH hypersecretion in tumors.
2016-12-01 | GSE83421 | GEO
Project description:Studies on human parathyroid tissue are often limited to adenomatous tissue due to difficulty obtaining healthy tissue. We obtained nonhuman primate parathyroids to provide a suitable alternative for sequencing analysis that would bear the closest semblance to human organs as possible. We analyzed four M. mulatta normal parathyroid specimens to that show a continuous trajectory of cell states comprising the normal adult parathyroid. We calculated the predicted pseudotime progression based on transcriptomic signatures that were reflective of repopulating progenitors, progressing to chief cells, and ultimately oxyphils, and clustered genes based on their expression dynamics along this axis. As a comparator, we histologically characterized and sequenced four human adenomas with varying oxyphil and chief cell abundance to highlight similarities and differences to normal parathyroid cell expression dynamics. We noted abundant RARRES2 transcripts that were detected in both human adenoma and normal primate parathyroid cells, and provided co-immunostaining validation of Chemerin presence in PTH-expressing cells, which could play a previously unrecognized role in parathyroid endocrine function.
2024-03-12 | GSE233962 | GEO
Project description:Stimulation of estrogen receptor beta in PHPT, genetic changes after 24 and 48h of treatments vs. Control Treatment of parathyroid adenomas (4 patients, 4 adenomas) with DPN 24h (4 samples), DPN 48h (4 samples), OHT 24h (4 samples), OHT 48h (4 samples), control 24h (3 samples), control 48h (4 samples). Omission of 1 sample based on low RNA quality.
2012-09-19 | E-GEOD-37211 | biostudies-arrayexpress
Project description:PurposeHyperparathyroidism is the third most common endocrine disease. Parathyroid adenoma (PA) accounts for approximately 85% of cases of primary hyperparathyroidism, but the molecular mechanism is not fully understood. Herein, we aimed to investigate the genetic and transcriptomic profiles of sporadic PA.MethodsWhole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) of 41 patients with PA and RNA-seq of 5 normal parathyroid tissues were performed. Gene mutations and characterized expression changes were identified. To elucidate the molecular mechanism underlying PA, unsupervised consensus clustering of RNA-seq data was performed. The correlations between the sequencing data and clinicopathological features of these patients were analyzed.ResultsPreviously reported PA driver gene mutations, such as MEN1 (9/41), mTOR (4/41), ZFX (3/41), CASR (3/41), EZH2 (2/41) and FAT1 (2/41), were also identified in our cohort. Furthermore, somatic mutation of EZH1, which had not been reported in PA, was found in 4 samples. RNA-seq showed that the expression levels of 84 genes were upregulated and 646 were downregulated in PA samples compared with normal samples. Unsupervised clustering analysis of RNA-seq data clustered these patients into 10 subgroups related to mutation or abnormal expression of a group of potential pathogenic genes.ConclusionMEN1, EZH2, CASR, EZH1, ZFX, mTOR and FAT1 mutations in PA were revealed. According to the RNA-seq data clustering analysis, cyclin D1, β-catenin, VDR, CASR and GCM2 may be important factors contributing to the PA gene expression profile.
| S-EPMC8163014 | biostudies-literature
Project description:The pathogenesis of primary hyperparathyroidism (I-HPT) and secondary hyperparathyroidism (II-PTH) remains to be elucidated. To characterize their pathophysiology, we investigated the effects of calcium and phosphate on cell proliferation and PTH release in an organ culture of parathyroid tissues. Dissected parathyroid tissues obtained from patients with I-HPT (adenoma) or II-PTH (nodular hyperplasia) were precultured on a collagen-coated membrane for 1-4 week. After exchanging the medium for one containing various concentrations of phosphate, PTH release and [3H]thymidine incorporation were studied. In contrast to dispersed parathyroid cells cultured in a monolayer, calcium decreased PTH release in a concentration-dependent manner in parathyroid tissues. Furthermore, when parathyroid tissues obtained from II-PTH were precultured for 1-4 weeks, PTH release and parathyroid cell proliferation were significantly increased in high-phosphate medium. These phosphate effects were also observed to a lesser extent in parathyroid tissues obtained from I-HPT, but there was no significant difference between I-HPT and II-HPT. Microarray analyses revealed that mRNA levels of PTH, CaSR, and VDR were well preserved, and several growth factors (e.g. TGF-beta1-induced protein) were abundantly expressed in II-PTH. Using organ cultures of hyperparathyroid tissues, in which PTH release and CaSR are well preserved for a prolonged period, we have demonstrated that phosphate stimulates parathyroid cell proliferation not only in II-PTH but also in I-HPT. Although the mechanism responsible for phosphate-induced cell proliferation remains to be elucidated, our in vitro findings suggest that both parathyroid tissues preserve to some extent a physiological response system to hyperphosphatemia as observed in normal parathyroid cells. These data will be published in Journal of Bone & Mineral Metabolism. Keywords: Organ culture experiments, dultured in low vs.high phosphate medium
2008-05-13 | GSE11423 | GEO
Project description:The pathogenesis of primary hyperparathyroidism (I-HPT) and secondary hyperparathyroidism (II-PTH) remains to be elucidated. To characterize their pathophysiology, we investigated the effects of calcium and phosphate on cell proliferation and PTH release in an organ culture of parathyroid tissues. Dissected parathyroid tissues obtained from patients with I-HPT (adenoma) or II-PTH (nodular hyperplasia) were precultured on a collagen-coated membrane for 1-4 week. After exchanging the medium for one containing various concentrations of phosphate, PTH release and [3H]thymidine incorporation were studied. In contrast to dispersed parathyroid cells cultured in a monolayer, calcium decreased PTH release in a concentration-dependent manner in parathyroid tissues. Furthermore, when parathyroid tissues obtained from II-PTH were precultured for 1-4 weeks, PTH release and parathyroid cell proliferation were significantly increased in high-phosphate medium. These phosphate effects were also observed to a lesser extent in parathyroid tissues obtained from I-HPT, but there was no significant difference between I-HPT and II-HPT. Microarray analyses revealed that mRNA levels of PTH, CaSR, and VDR were well preserved, and several growth factors (e.g. TGF-beta1-induced protein) were abundantly expressed in II-PTH. Using organ cultures of hyperparathyroid tissues, in which PTH release and CaSR are well preserved for a prolonged period, we have demonstrated that phosphate stimulates parathyroid cell proliferation not only in II-PTH but also in I-HPT. Although the mechanism responsible for phosphate-induced cell proliferation remains to be elucidated, our in vitro findings suggest that both parathyroid tissues preserve to some extent a physiological response system to hyperphosphatemia as observed in normal parathyroid cells. These data will be published in Journal of Bone & Mineral Metabolism. Experiment Overall Design: Two conditioned experimets, low vs. high phosphate medium, cultured for 1 and 4 days
2008-06-20 | E-GEOD-11423 | biostudies-arrayexpress
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas.
2012-05-01 | GSE32387 | GEO
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas. Expression profiling was done in parathyroid adenomas subjected to prolactin treatment in culture. In addition, corresponding paraffin sections were obtained for verification of PRLr expression by immunohistochemistry. 200 mg/L prolactin (recombinant humanM-BM- prolactin, Cat. No. JM-4687-50, MBL Woburn, MA) was added to 1M-CM-^W 10^6 attached parathyroid tumour cells. Cells were harvested using RNAlater (QIAGEN) and homogenized with QIAshredder for RNA extraction after 3 h and 24 h in culture, respectively. Negative controls were collected in parallel with each case at the same time points. RNA was extracted using QIA Cube, and quality assessed with Bioanalyser and Nanodrop. Expression array profiling and data analysis was done at the KI core facility Bioinformatics and Expression Analysis (BEA, Novum, Huddinge) using the Affymetrix platform and the TITAN ST 1.1 array. A total of 16 samples were analysed including 4 parathyroid adenomas cultured for 3 h or 24 h in the presence of prolactin plus control samples cultured in parallel without prolactin.
2012-04-30 | E-GEOD-32387 | biostudies-arrayexpress
Project description:Activating mutations in kinase/PI3K/RAS signaling pathways are common in acute leukemia with KMT2A rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remain unclear. Using a retroviral acute myeloid leukemia model, we demonstrate that NRASG12D, FLT3ITD, and FLT3N676K accelerates KMT2A-MLLT3 leukemia onset. Importantly, also the presence of subclonal FLT3N676K in KMT2A-R leukemic cells shorten disease latency, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 driven leukemia and favored clonal expansion. KMT2A-MLLT3 leukemia with an activating mutation enforce Myc- and Myb transcriptional modules, whereas KMT2A-MLLT3 leukemias lacking activating mutations displayed upregulation of signal transduction pathways. Our results provide new insight into the biology of KMT2A-R leukemia and highlights the importance of activated signaling as a contributing driver in this disease.
2018-05-02 | PXD008213 | Pride