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Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming [RNA-seq]

ABSTRACT: Although it is known that the uterine fibroid linked MED12 mutations disrupt the CDK8/19 kinase activity, how CDK8/19 disruption contributes to making the myometrial stem cell tumorigenic and form uterine fibroids. This study seeks to determine the molecular consequences of pharmacologically disrupting mediator kinase activity in myometrial stem cells, the presumptive cell of origin for uterine fibroids, through parallel transcriptomic and epigenomic profiling by bulk RNA-seq and H3K27ac CUT&RUN.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276459 | GEO | 2025/02/12

REPOSITORIES: GEO

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Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming [CUT&RUN]

Project description:Although it is known that the uterine fibroid linked MED12 mutations disrupt the CDK8/19 kinase activity, how CDK8/19 disruption contributes to making the myometrial stem cell tumorigenic and form uterine fibroids. This study seeks to determine the molecular consequences of pharmacologically disrupting mediator kinase activity in myometrial stem cells, the presumptive cell of origin for uterine fibroids, through parallel transcriptomic and epigenomic profiling by bulk RNA-seq and H3K27ac CUT&RUN.

2025-02-12 | GSE276458 | GEO

Uterine Fibroid and Normal Myometrial Expression Profiles- U133 Arrays

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. Keywords: other

2003-10-17 | GSE593 | GEO

Transcriptome of human myometrial stem cells in the context of uterine fibroids

Project description:Our study represents a new strategy for identifying drivers and risk factors of uterine fibroids (F) by identifying genes and pathways differentially regulated in myometrial stem cells (SCs) isolated from myometrium without fibroids (MyoN) and from myometrium adjacent to uterine fibroids (MyoF) using RNA-seq approach. Moreover, we will perform the comparison analysis of the transcriptome between MyoF SCs and fibroid SCs to identify differentially expressed genes.

2023-09-24 | GSE158515 | GEO

Transcription profiling of human uterine fibroid (leiomyoma) and normal myometrial tissue to identify differentially expressed genes

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

HMGA2 overexpression induces plasticity in myometrial cells and a transcriptomic profile more similar to that of uterine fibroids

Project description:Objective: To study the possible role for HMGA2 overexpression in differentiated myometrial cells and its potential to induce a stem cell-like or dedifferentiating phenotype and drive fibroid development. Design: Myometrial cells were immortalized and transduced with an HMGA2 lentivirus to produce HMGA2hi cells. In vitro stem cell assays were conducted, and ribonucleic acid from HMGA2hi and control cells as well as fibroid-free myometrial and HMGA2 fibroid (HMGA2F) tissues were submitted for ribonucleic acid sequencing. Setting: University research laboratory. Patient(s): Women who underwent hysterectomy for symptomatic uterine fibroids or other gynecological conditions. Intervention(s): Not applicable. Main Outcome Measure(s): In vitro stem cell-like properties from myometrial cell lines. Ribonucleic acid sequencing and collagen production of HMGA2-overexpressing primary leiomyoma tissue and cell lines. Result(s): HMGA2hicellshadenhancedself-renewalcapacity,decreasedproliferation,andagreaterabilitytodifferentiateintoother mesenchymal cell types. HMGA2hi cells exhibited a stem cell-like signature and shared transcriptomic similarities with HMGA2F. Moreover, dysregulated extracellular matrix pathways were observed in both HMGA2hi cells and HMGA2F. Conclusion(s): Our findings show that HMGA2 overexpression may drive myometrial cells to dedifferentiate into a more plastic phenotype and provide evidence for an alternative mechanism for fibroid etiology, suggesting that fibroids arise not only from a mutated stem cell but also from a mutated differentiated myometrial cell.

2024-08-14 | GSE268710 | GEO

Transcriptome and DNA Methylome Analyses Reveal Underlying Mechanisms for the Racial Disparity in Uterine Fibroids [EPIC Human Methylation Array]

Project description:Genome wide DNA methylation profiling of normal myometrial and fibroid samples. Uterine fibroids (leiomyomas) affect Black women disproportionately in terms of prevalence, incidence, and severity of symptoms. The causes of this racial disparity are essentially unknown. We hypothesized that myometria of Black women are more susceptible to developing fibroids and examined the transcriptomic and DNA methylation profiles of myometria and fibroids from Black and White women for comparison. Myometrial samples cluster by race in both their transcriptome and DNA methylation profiles, whereas fibroid samples only cluster by race in the latter. More differentially expressed genes (DEGs) were detected in the Black and White myometrial comparison than in the fibroid comparison. Leiomyoma gene set expression analysis showed four different clusters of DEGs, including a cluster with highest expression in Black myometrial samples and elevated in all fibroids. One of the DEGs in this group, VWF, was significantly hypomethylated at two CpG probes near a putative enhancer site in Black myometrial and in all fibroid samples compared with White myometrial samples, suggesting that VWF expression is responsive to DNA hypomethylation, a known stress response. These results suggest that the molecular basis for the disparity in fibroid disease between Black and White women could be found in the myometria before fibroid development and not in the fibroids themselves.

2022-09-21 | GSE207349 | GEO

Transcriptome Analyses of Myometrium from Fibroid Patients Reveals Phenotypic Differences Compared to Non-diseased Myometrium

Project description:Uterine fibroid tissues are often compared to their matched myometrium in an effort to understand their pathophysiology, but it is not clear whether the myometria of uterine fibroid patients represent truly non-disease control tissues. We analyzed the transcriptomes of myometrial samples from non-fibroid patients (M) and from matched myometrial (MF) and fibroid (F) samples to determine whether there is a phenotypic difference between fibroid and non-fibroid myometria. Multidimensional scaling plots revealed that M samples clustered separately from both MF and F samples. A total of 1,169 differentially expressed genes (DEGs) (false discovery rate < 0.05) were observed in the MF comparison with M. Overrepresented Gene Ontology terms showed a high concordance of upregulated gene sets in MF compared to M, particularly extracellular matrix and structure organization. Gene set enrichment analyses showed that the leading-edge genes from the TGFβ signaling and inflammatory response gene sets were significantly enriched in MF. Overall comparison of the three tissues by three-dimensional principal component analyses showed that M, MF, and F samples clustered separately from each other and that a total of 732 DEGs from F vs M were not found in the F vs MF, which are likely understudied in the pathogenesis of uterine fibroids. These results suggest that the transcriptome of MF tissues are different from non-diseased myometrial tissues. Many dysregulated genes were not included in the F vs MF DEGs and may contain key genes for future investigations suggesting that fibroid studies should consider using not only matched myometrium but also non-diseased myometrium as the control.

2021-03-21 | GSE169255 | GEO

Transcriptome and DNA Methylome Analyses Reveal Underlying Mechanisms for the Racial Disparity in Uterine Fibroids [RNA-seq]

Project description:Uterine fibroids (leiomyomas) affect Black women disproportionately in terms of prevalence, incidence, and severity of symptoms. The causes of this racial disparity are essentially unknown. We hypothesized that myometria of Black women are more susceptible to developing fibroids and examined the transcriptomic and DNA methylation profiles of myometria and fibroids from Black and White women for comparison. Myometrial samples cluster by race in both their transcriptome and DNA methylation profiles, whereas fibroid samples only cluster by race in the latter. More differentially expressed genes (DEGs) were detected in the Black and White myometrial comparison than in the fibroid comparison. Leiomyoma gene set expression analysis showed four different clusters of DEGs, including a cluster with highest expression in Black myometrial samples and elevated in all fibroids. One of the DEGs in this group, VWF, was significantly hypomethylated at two CpG probes near a putative enhancer site in Black myometrial and in all fibroid samples compared with White myometrial samples, suggesting that VWF expression is responsive to DNA hypomethylation, a known stress response. These results suggest that the molecular basis for the disparity in fibroid disease between Black and White women could be found in the myometria before fibroid development and not in the fibroids themselves.

2022-09-21 | GSE207209 | GEO

Analysis of the purified RNA samples to confirm that Notch pathway activation inhibits apoptosis in uterine leiomyomas leading to fibroid growth

Project description:Uterine leiomyomas are the most common benign tumor in humans causing significant morbidity with vaginal bleeding, pelvic pressure and pain. Histologically, leiomyomas show a large degree of extracellular matrix disorganization. I am working with a colleague who recently found Notch pathway gene expression were clearly altered in fibroids (“Differential expression of the Notch signal transduction pathway: ligands, receptors and Numb in uterine leiomyomas vs. myometrium,” G. Christman, H. Tang, I. Ahmad, J. Stribley, Fertility and Sterility, Volume 88, Supp 1, S72, September 2007). Glycosaminoglycan expression was found to be over-expressed in uterine leiomyomas compared to myometrial samples (Fertility and Sterility, Vol 88 Supp 1, S106, September, 2007), but glycosyltransferase and glycosidase expression has not been reported. We have purified RNA samples from paired uterine leiomyoma and normal myometrium from a previous clinical study. Dr. Domino's laboratory hypothesis is that Notch pathway activation inhibits apoptosis in uterine leiomyomas leading to fibroid growth. Notch ligands are fucosylated glycans. The bulk of a fibroid is the extracellular matrix yet little has been studied on leiomyocyte expression of enzymes that model glycans in the extracellular matrix. RNA preparations of paired samples of excess human tissues from hysterectomies, with two different groups normal myometrium, and leiomyoma tumors were sent to Microarray Core (E). The RNA was amplified, labeled, and hybridized to GLYCO_v3 microarrays.

2011-04-29 | E-GEOD-28945 | biostudies-arrayexpress

Analysis of the purified RNA samples to confirm that Notch pathway activation inhibits apoptosis in uterine leiomyomas leading to fibroid growth

2011-04-29 | GSE28945 | GEO