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Project description:Uterine leiomyoma (LM) is the most common tumor in women and can cause severe morbidity. Leiomyoma growth requires the maintenance and proliferation of a stem cell population. Dysregulated deoxyribonucleic acid (DNA) methylation has been reported in LM, but its role in LM stem cell regulation remains unclear. Here, we fluorescence-activated cell sorting (FACS)-sorted cells from human LM tissues into 3 populations: LM stem cell-like cells (LSC, 5%), LM intermediate cells (LIC, 7%), and differentiated LM cells (LDC, 88%), and we analyzed the transcriptome and epigenetic landscape of LM cells at different differentiation stages. Leiomyoma stem cell-like cells harbored a unique methylome, with 8862 differentially methylated regions compared to LIC and 9444 compared to LDC, most of which were hypermethylated. Consistent with global hypermethylation, transcript levels of TET1 and TET3 methylcytosine dioxygenases were lower in LSC. Integrative analyses revealed an inverse relationship between methylation and gene expression changes during LSC differentiation. In LSC, hypermethylation suppressed the genes important for myometrium- and LM-associated functions, including muscle contraction and hormone action, to maintain stemness. The hypomethylating drug, 5'-Aza, stimulated LSC differentiation, depleting the stem cell population and inhibiting tumor initiation. Our data suggest that DNA methylation maintains the pool of LSC, which is critical for the regeneration of LM tumors.
| S-EPMC7497820 | biostudies-literature
Project description:Targeting DNA Methylation Depletes Uterine Leiomyoma Stem Cell-enriched Population by Stimulating Their Differentiation
| PRJNA574303 | ENA
Project description:BackgroundUterine 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 remains unknown.Principal findingsWe 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 between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels.ConclusionsThese results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women.
| S-EPMC3302826 | biostudies-literature
Project description:Differential diagnosis of uterine leiomyomas and leiomyosarcomas is needed to determine whether the uterus can be retained. Therefore, biomarkers for uterine leiomyomas, and reliable and objective diagnostic methods have been desired besides the pathological diagnosis. In the present study, we identified 12 genes specific to uterine leiomyomas based on DNA methylation. Using these marker genes specific to uterine leiomyomas, we established a hierarchical clustering system based on the DNA methylation level of the marker genes, which could completely differentiate between uterine leiomyomas and normal myometrium. Furthermore, our hierarchical clustering system completely discriminated uterine cancers and differentiated between uterine leiomyosarcomas and leiomyomas with more than 70% accuracy. In conclusion, this study identified DNA methylation-based marker genes specific to uterine leiomyomas, and our hierarchical clustering system using these marker genes was useful for differential diagnosis of uterine leiomyomas and leiomyosarcomas.
| S-EPMC4976337 | biostudies-literature
Project description:Uterine leiomyoma (LM) is the most common tumor in women. Via its receptor (PGR) expressed in differentiated LM cells, progesterone stimulates paracrine signaling that induces proliferation of PGR-deficient LM stem cells (LSCs). Antiprogestins shrink LM but tumors regrow after treatment cessation possibly due to persisting LSCs. Using sorted primary LM cell populations, we found that the PGR gene locus and its target cistrome are hypermethylated in LSCs, inhibiting the expression of genes critical for progesterone-induced LSC differentiation. PGR knockdown shifted the transcriptome of total LM cells toward LSCs and increased global DNA methylation by regulating TET methylcytosine dioxygenases. DNA methylation inhibitor 5'-Aza activated PGR signaling, stimulated LSC differentiation, and synergized with antiprogestin to reduce tumor size in vivo. Taken together, targeting the feedback loop between DNA methylation and progesterone signaling may accelerate the depletion of LSCs through rapid differentiation and sensitize LM to antiprogestin therapy, thus preventing tumor regrowth.
| S-EPMC8452515 | biostudies-literature
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:The purpose of this work was to engineer polymeric nanoparticles to encapsulate and deliver 2-methoxyestradiol, a potential antitumor drug for treatment of uterine leiomyoma (fibroids), the most common hormone-dependent pathology affecting women of reproductive age.Encapsulation efficiency and drug release from the nanoparticles were monitored by HPLC. Cell morphology and in vitro cytotoxicity experiments were carried out in a human leiomyoma cell line. The nanoparticles displayed high encapsulation efficiency (>86%), which was verified by differential scanning calorimetry and x-ray diffraction. Excellent long-term stability of the nanoparticles and gradual drug release without burst were also observed. Cellular uptake of fluorescent nanoparticles was confirmed by confocal imaging. The drug-loaded poly(lactic acid) and poly(lactic-co-glycolic acid) nanoparticles induced cytotoxicity in human leiomyoma cells to a significantly greater extent than the free drug at 0.35 µM.This novel approach represents a potential fertility-preserving alternative to hysterectomy.
| S-EPMC3754434 | biostudies-literature
Project description:Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10-25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.
| S-EPMC6985131 | biostudies-literature
Project description:Uterine leiomyomas (LM) affect up to 80% of all reproductive-age women. LM growth requires progesterone, progesterone receptor (PGR), and the maintenance and proliferation of a small (5%) stem cell population. Stem cell activation and differentiation are driven by DNA methylation and nuclear hormone receptor action, but crosstalk between these mechanisms remains unclear. We performed an integrated analysis of the transcriptome and epigenetic landscape of LM cells at three differentiation stages and the PGR cistrome of whole LM tissue. The PGR-deficient stem cell population harbored a unique methylation landscape, with hypermethylation at the PGR gene locus and PGR-binding regions, which suppressed stem cell responsiveness to progesterone. The DNA methylation inhibitor 5’-Aza upregulated the expression of PGR and its target genes by stimulating PGR recruitment to the targeted gene loci, and significantly depleted the LM stem cell population and its tumor-initiating capacity. We herein provided mechanistic insights via therapeutically accelerating the stem cell differentiation process of a hormone-sensitive tumor.
2020-10-01 | GSE138047 | GEO
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