Single-cell atlas of the leiomyoma microenvironment reveals hallmarks of myometrial vascular inflammation
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PROVIDER: PRJNA910588 | ENA |
REPOSITORIES: ENA
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Project description:Uterine fibroids or leiomyoma are benign smooth muscle-derived tumours and are the most common pelvic uterine tumours of women in reproductive age. Large numbers of patients present with symptoms of heavy or prolonged menstrual bleeding, dyspareunia, pelvic pain, miscarriage, and infertility. The underlying causes are not understood; however it is hypothesized that fibroid-uterine interactions orchestrate clinical sequelae, mediated through the pseudocapsule, an anatomical entity that surrounds the myoma and separates it from normal myometrium. We here present a single cell atlas of the uterine pseudocapsule architecture by integrating single nuclei transcriptomics with highly multiplexed immunofluorescence imaging. The data suggest vascular inflammation leading to substantial infiltration of activated innate and adaptive immune cells in the pseudocapsule and we map fibroblast/stromal and endothelial cell activation states and interactions. The results advance our understanding of molecular events underlying leiomyoma pathology and provide novel insights into aberrant and actionable immunological processes occurring in the tumour microenvironment.
2025-08-06 | GSE220650 | GEO
Project description:With the utilization of advanced tools for genome-wide studies, the role of the epigenome in regulating gene expression is becoming more evident in both normal tissue development and disease states. Uterine fibroids, also known as leiomyomas, are a major reproductive disease that manifests as benign tumors and altered extracellular matrix composition leading to severe pathological symptoms. Several genomic alterations have been associated with leiomyoma. HMGA2 overexpression has been noted in approximately 10% of all patients with leiomyoma. HMGA2 is a chromatin-targeted protein and is therefore an important contributor to altered transcriptomic outcomes. However, due to a lack of specific antibodies against HMGA2 and appropriate in vitro cellular models, there is a lack in understanding of HMGA2 interaction with and regulation of chromatin in the context of leiomyoma. To address this gap, we engineered primary myometrial cells that express V5-tagged HMGA2 at levels comparable to those observed in leiomyoma. We observed transcriptomic and H3K27 acetylation changes that appeared to drive a leiomyoma-like phenotype in the engineered HMGA2v5 cells. HMGA2 was found to be diffusedly bound to chromatin, with most of the binding occurring at promoter- distal regions. Moreover, altered chromatin accessibility was observed in HMGA2v5 cells, with enrichment of AP-1 family transcription factor binding motifs at various sites. Thus, our study suggests that overexpression of HMGA2 modulates the genomic architecture of myometrial cells to cause leiomyoma-like gene expression and epigenomic changes.
2025-10-01 | GSE276285 | GEO
Project description:With the utilization of advanced tools for genome-wide studies, the role of the epigenome in regulating gene expression is becoming more evident in both normal tissue development and disease states. Uterine fibroids, also known as leiomyomas, are a major reproductive disease that manifests as benign tumors and altered extracellular matrix composition leading to severe pathological symptoms. Several genomic alterations have been associated with leiomyoma. HMGA2 overexpression has been noted in approximately 10% of all patients with leiomyoma. HMGA2 is a chromatin-targeted protein and is therefore an important contributor to altered transcriptomic outcomes. However, due to a lack of specific antibodies against HMGA2 and appropriate in vitro cellular models, there is a lack in understanding of HMGA2 interaction with and regulation of chromatin in the context of leiomyoma. To address this gap, we engineered primary myometrial cells that express V5-tagged HMGA2 at levels comparable to those observed in leiomyoma. We observed transcriptomic and H3K27 acetylation changes that appeared to drive a leiomyoma-like phenotype in the engineered HMGA2v5 cells. HMGA2 was found to be diffusedly bound to chromatin, with most of the binding occurring at promoter- distal regions. Moreover, altered chromatin accessibility was observed in HMGA2v5 cells, with enrichment of AP-1 family transcription factor binding motifs at various sites. Thus, our study suggests that overexpression of HMGA2 modulates the genomic architecture of myometrial cells to cause leiomyoma-like gene expression and epigenomic changes.
2025-10-01 | GSE276287 | GEO
Project description:High-mobility group AT-hook 2 is a non-histone chromatin binding nuclear protein that belongs to the high-mobility group A family, which are known as "architectural transcription factors". Overexpression of HMGA2, resulting primarily due to chromosomal rearrangements of 12q15 loci, is considered a driver event in approximately 10% of uterine leiomyoma cases. To better understand how HMGA2 overexpression contributes to the formation of uterine leiomyoma, we generated primary myometrial cells engineered to overexpress HMGA2 (n=3) and determined the effect of HMGA2-overexpression on genome-wide mRNA levels, H3K27ac deposition, and chromatin accessibility.
2025-10-01 | GSE276286 | GEO
Project description:The goal of this study was to select the optimal myometrial cells for our high-throughput drug discovery assay, as well as determine the similarity or differences of myometrial cells to vascular smooth muscle cells (VSMCs)-the most common off-target of current myometrial therapeutics. RNA-seq was used to: 1) identify which myometrial cells retained the most similar transcriptome profile to native tissue, and 2) compare the uterine myometrial transcriptome to VSMCs in hopes of identifying a uterine-selective transcriptome that was “druggable” for tocolytic or uterotonic use. Four sources of myometrial cells were examined: 1) term pregnant human primary myometrial cells isolated from tissue biopsies obtained at the time of caesarean sections, 2) term pregnant mouse primary myometrial cells, 3) commercially-available immortalized pregnant human myometrial (PHM1) cells and 4) human telomerase immortalized myometrial (hTERT-HM) cells. Correlation analysis of aligned reads identified that the transcriptome of primary human myometrial and hTERT-HM cells showed 85% and 80% correlation, respectively, to human myometrial tissue and that the transcriptome of hTERT-HM and PHM1 cells is 90% or more correlative to human primary myometrial cells. The expression levels (fold-change) of contraction-associciated transcripts (OXTR, PTGFR, PTGS2 and GJA1) strongly correlated (r=0.93) between RNA sequencing and qRT-PCR analysis. Analysis of aligned reads among myometrial cells revealed the number of differentially expressed transcripts (fold-change≥2.0, adjusted p-value≤0.01) relative to primary human myometrial cells: hTERT-HM (946 upregulated and 2,351 downregulated), PHM1 (1,575 upregulated and 2,415 downregulated) and primary mouse myometrial cells (3,435 upregulated and 2,966 downregulated). Correlation analysis showed that the human primary myometrial cell transcriptome is over 90% similar to the transcriptome of VSMCs examined. A number of genes associated with smooth muscle contractile machinery (TPM1, TPM2, CNN1, CALD1, ACTA2 and PLN)were significantly (p≤0.01) upregulated (≥2-fold) in human primary myometrial compared to vascular SMCs. We identified 498 transcripts were identified as upregulated in human primary myometrial cells compared to all three VSMCs examined. Of these, the drug-gene interaction database identified 142 genes as druggable
2020-04-14 | GSE125701 | GEO
Project description:Our study seeks to identify genes differentially expressed between uterine leiomyomas and normal myometrial tissue. This series consists of samples derived from normal myometrium and uterine leiomyomas obtained from fibroid afflicted patients.Total RNA was extracted from samples, converted to biotin-labeled cRNA, hybridized to oligonucleotide arrays, and followed by model based expression analysis.,In order to select differentially expressed genes of interest, dChip model-based expression analysis was employed. Significant genes were identified, utilizing the dChip software, as having an average fold change of > +1.5 or < -1.5 between leiomyoma and normal myometrium and p < 0.05. Under these conditions the 226 genes in the following list were identified.
2007-09-28 | E-GEOD-593 | biostudies-arrayexpress
Project description:Comparative transcriptome profiling myometrial and vascular smooth muscle cells
| PRJNA517268 | ENA
Project description:Uterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities, however, remains unknown. Principal Findings: We characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African-American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected two genes, the known tumor suppressors KLF11 and DLEC1, and verified promoter hypermethylation and mRNA repression using bisulfite sequencing and real-time PCR. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11 and DLEC1 mRNA levels. paired LM and MM tissue samples
2012-04-29 | E-GEOD-31699 | biostudies-arrayexpress
Project description:Uterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities, however, remains unknown. Principal Findings: We characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African-American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected two genes, the known tumor suppressors KLF11 and DLEC1, and verified promoter hypermethylation and mRNA repression using bisulfite sequencing and real-time PCR. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11 and DLEC1 mRNA levels.
2012-04-30 | GSE31699 | GEO