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

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

PROVIDER: PRJNA933271 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23387710_1.fastq.gz	Fastqsanger.gz
	SRR23387710_2.fastq.gz	Fastqsanger.gz
	SRR23387711_1.fastq.gz	Fastqsanger.gz
	SRR23387711_2.fastq.gz	Fastqsanger.gz
	SRR23387712_1.fastq.gz	Fastqsanger.gz

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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

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 Transcripts in Uterine Leiomyomas.

Project description:Recent studies have demonstrated that somatic MED12 mutations in exon 2 occur at a frequency of up to 80% and have a functional role in leiomyoma pathogenesis. The objective of this study was to elucidate the expression profile of coding RNA transcripts in leiomyomas, with and without these mutations, and their paired myometrium. Next-generation RNA sequencing (NGS) was used to systematically profile the differentially expressed RNA transcripts from paired leiomyomas (n = 19). The differential analysis indicated there are 394 genes differentially and aberrantly expressed only in the mutated tumors. These genes were predominantly involved in the regulation of extracellular constituents. Of the differentially expressed genes that overlapped in the two comparison groups, the magnitude of change in gene expression was greater for many genes in tumors bearing MED12 mutations. Although the myometrium did not express MED12 mutations, there were marked differences in the transcriptome landscape of the myometrium from mutated and non-mutated specimens, with genes regulating the response to oxygen-containing compounds being most altered. In conclusion, MED12 mutations have profound effects on the expression of genes pivotal to leiomyoma pathogenesis in the tumor and the myometrium which could alter tumor characteristics and growth potential.

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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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Project description:Pathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs). An integrated proteogenomic analysis of ULMs from HLRCC (n=16; FH-mutation confirmed) and non-syndromic (NS) patients (n=12) identified a significantly higher protein:transcript correlation in HLRCC (R=0.35) vs. NS ULMs (R=0.242, MWU p=0.0015). Co-altered proteins and transcripts (228) included antioxidant response element (ARE) target genes, such as thioredoxin reductase 1 (TXNRD1), and correlated with activation of NRF2-mediated oxidative stress response signaling in HLRCC ULMs. We confirm 185 transcripts previously described as altered between HLRCC and NS ULMs, 51 co-altered at the protein level and several elevated in HLRCC ULMs are involved in regulating cellular metabolism and glycolysis signaling. Furthermore, 367 S-(2-succino)cysteine peptides were identified in HLRCC ULMs, of which sixty were significantly elevated in HLRCC vs. NS ULMs (LogFC=1.86, MWU p<0.0001). These results confirm and define novel proteogenomic alterations in uterine leiomyoma tissues collected from HLRCC patients and underscore conserved molecular alterations correlating with inactivation of the FH tumor suppressor gene.

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Differential Expression of Super-enhancer-associated Long Non-coding RNAs in Uterine Leiomyomas

Project description:Differential Expression of Super-enhancer-associated Long Non-coding RNAs in Uterine Leiomyomas

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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

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