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Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

ABSTRACT: Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

PROVIDER: PRJNA526890 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10363200.fastq.gz	Fastqsanger.gz
	SRR10363201.fastq.gz	Fastqsanger.gz
	SRR10363202.fastq.gz	Fastqsanger.gz
	SRR10363203.fastq.gz	Fastqsanger.gz
	SRR10363204.fastq.gz	Fastqsanger.gz

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Comparison of Gene expression profiles between myometrium, MED12 mutation positive uterine leiomyomas and MED12 wildtype uterine leiomyomas

Project description:Gene expression profiles of 10 uterine leiomyomas and their matched normal myometrium specimens were studied using Affymetrix GeneChip Human Genome U133 Plus 2.0 gene expression arrays. Four tumors displayed a codon 44 mutation, four carried a intron 1 mutation, and the remaining two displayed no MED12 mutation.

2011-08-26 | GSE30673 | GEO

Differential Expression of MED12-Associated Coding RNA 2 transcripts in Uterine Leiomyomas

Project description:The objective of this study was to elucidate the expression profile of coding RNA transcripts in leiomyomas with and without MED12 mutation and their paired myometrium.

2023-03-01 | GSE224991 | GEO

Differential Expression of MED12-Associated Coding RNA 2 transcripts in Uterine Leiomyomas

Project description:Differential Expression of MED12-Associated Coding RNA 2 transcripts in Uterine Leiomyomas

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Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas.

Project description:Uterine leiomyomas (fibroids) are a major source of gynecologic morbidity in reproductive age women and are characterized by the excessive deposition of a disorganized extracellular matrix, resulting in rigid benign tumors. Although down regulation of the transcription factor AP-1 is highly prevalent in leiomyomas, the functional consequence of AP-1 loss on gene transcription in uterine fibroids remains poorly understood. Using high-resolution ChIP-sequencing, promoter capture Hi-C, and RNA-sequencing of matched normal and leiomyoma tissues, here we show that modified enhancer architecture is a major driver of transcriptional dysregulation in MED12 mutant uterine leiomyomas. Furthermore, modifications in enhancer architecture are driven by the depletion of AP-1 occupancy on chromatin. Silencing of AP-1 subunits in primary myometrium cells leads to transcriptional dysregulation of extracellular matrix associated genes and partly recapitulates transcriptional and epigenetic changes observed in leiomyomas. These findings establish AP-1 driven aberrant enhancer regulation as an important mechanism of leiomyoma disease pathogenesis.

| S-EPMC7040020 | biostudies-literature

MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas

Project description:Uterine leiomyoma (LM) is the most common tumor in women. Estrogen and progesterone, via their receptors ERα and PR, play essential roles in LM growth. Mediator complex subunit 12 (MED12) mutations occur in 70% of all LM and are thought to drive tumor growth in a steroid hormone-dependent manner; however, the mechanisms remain unclear. Here, we performed ChIP-seq (ERα, PR, and MED12) and RNA-seq on LM expressing mutant MED12 (mut-MED12) or wild-type MED12 and matched myometrium. Mut-MED12 altered PR and chromatin interaction landscapes, with significant PR-binding site loss in proximal promoter regions in mut-MED12 LM. Integration of cistrome and transcriptome data identified tryptophan 2,3-dioxygenase (TDO2) as a PR and MED12 target gene, which was aberrantly upregulated in mut-MED12 LM. Kynurenine, the catabolic product of TDO2, was significantly elevated in mut-MED12 LM. Tryptophan or kynurenine treatment of primary LM cells activated the aryl hydrocarbon receptor (AHR) pathway, increased cell proliferation, and inhibited apoptosis; blocking the TDO2-kynurenine-AHR pathway by siRNA knockdown or pharmacologic inhibition abolished these effects. Mut-MED12 LM cells showed higher sensitivity to these treatments. These findings suggest that activation of the TDO2-kynurenine-AHR pathway in mut-MED12 LM induces tumor growth, and may inform the development of targeted treatments and precision medicine in LM.

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MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas

Project description:MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas

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Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-01-01 | GSE128242 | 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.

2011-04-29 | GSE28945 | GEO

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

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

Profiling and Functional Analyses of MicroRNAs and Their Target Gene Products in Human Uterine Leiomyomas

Project description:Human uterine leiomyomas (ULM) are characterized by dysregulation of a large number of genes and non-coding regulatory microRNAs. In order to identify microRNA::mRNA associations relevant to ULM pathogenesis, we examined global correlation patterns between the altered microRNA expression and the predicted target genes in leiomyomas and matched myometria. We found that some but not all of the predicted and inversely correlated target genes in ULMs can be directly regulated by microRNAs in vitro. Our findings provide a broad overview of molecular events underlying the tumorigenesis of uterine leiomyoma and identify select genetic and regulatory events that alter microRNA expression and may play important roles in ULM pathobiology by positively regulating tumor growth while maintaining the non-invasive character of ULMs Keywords: Differential gene expression Paired normal (myometrium) and tumor (ULM) samples derived from 5 patients were used

2010-07-24 | E-GEOD-23112 | biostudies-arrayexpress

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