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MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma.

ABSTRACT: MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma.

PROVIDER: PRJNA842908 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19428800.fastq.gz	Fastqsanger.gz
	SRR19428801.fastq.gz	Fastqsanger.gz
	SRR19428802.fastq.gz	Fastqsanger.gz
	SRR19428803.fastq.gz	Fastqsanger.gz
	SRR19428807.fastq.gz	Fastqsanger.gz

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MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma [RNA-seq]

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.

2023-05-01 | GSE204969 | GEO

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

2023-05-01 | GSE204968 | GEO

MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma [RNA-seq]

Project description:MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma [RNA-seq]

| PRJNA842912 | ENA

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

| PRJNA842913 | ENA

MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma.

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

2023-05-01 | GSE204970 | GEO

The aryl hydrocarbon receptor binds to kynurenine and mediates a signal supports the undifferentiated state in pluripotent stem cells

Project description:Kynurenine is generated from tryptophan by indoleamine 2,3-dioxygenase (IDO1) and binds to the aryl hydrocarbon receptor (AhR). We found that kynurenine generated by human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) stimulated the AhR to bind selectively to the promoters and enhancers of self-renewal genes, thus enhancing their transcription. The kynurenine-AhR complex also directly stimulated the expression of IDO1 and AHR, activating a positive feedback loop. Substantial amounts of kynurenine that were not complexed with AhR were present in the culture medium, providing a paracrine signal for maintenance of the undifferentiated state. Kynurenine was not present in the medium of differentiated ESCs and iPSCs. When cells were induced to undergo ectodermal differentiation, the abundance of kynurenine in the medium was reduced through activation of the main kynurenine catabolic pathway mediated by aminotransferase 2 (KAT2), resulting in the secretion of 2-aminoadipic acid (2-AAA) into the culture medium. Thus, kynurenine in the culture medium is a biomarker for the undifferentiated state, and 2-AAA in the culture medium is a biomarker for ESCs and iPSCs that have committed to differentiate along the ectoderm lineage.

2019-06-09 | GSE129507 | GEO

Engineered MED12 mutations drive uterine fibroid-like transcriptional and metabolic programs by altering the 3D genome compartmentalization [MED12_G44N_spheroid_RNA_seq]

Project description:We employed CRISPR knock-in with a sensitive PCR-based screening strategy to precisely engineer cells with mutant MED12 Gly44. Critically, the engineered myometrial SMC cells recapitulate several UF-like cellular, transcriptional and metabolic alterations, including enhanced proliferation rates in 3D spheres and altered Tryptophan/kynurenine. metabolism

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Engineered MED12 mutations drive uterine fibroid-like transcriptional and metabolic programs by altering the 3D genome compartmentalization [MED12_G44N_2D_RNA_seq]

2023-06-16 | GSE226014 | GEO