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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE226015 | GEO | 2023/06/16

REPOSITORIES: GEO

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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

2023-06-16 | GSE226016 | GEO

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

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

2023-06-16 | GSE226013 | GEO

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.

2023-05-01 | GSE204968 | GEO

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

2023-05-01 | GSE204969 | GEO

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

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

2023-06-16 | GSE226017 | GEO

Med12 and p300 chips in HSPCs

Project description:We characterized the genome wide occupancy of Med12 and p300 in mouse HSPCs. We also characterize p300 occupancy upon shRNA against control or Med12. ChIP-seq analysis of Med12 and/or p300 in untreated HSPCs

2016-08-25 | E-GEOD-76053 | biostudies-arrayexpress

Med12 and p300 chips in HSPCs

Project description:We characterized the genome wide occupancy of Med12 and p300 in mouse HSPCs. We also characterize p300 occupancy upon shRNA against control or Med12.

2016-08-25 | GSE76053 | GEO

Towards an Understanding of the Pathomechanisms of Uterine Fibroids

Project description:Uterine fibroids (UFs) are benign tumours affecting up to 80% of women of reproductive age. Although mutations in MED12 or HMGA2 account for the majority of UF occurrence, the processes by which these lead to UFs remain poorly understood. Here we present a comprehensive systems biology study, merging clinical, genetic, transcriptomic and proteomic information to better understand the patho-mechanisms underlying UF.

2022-05-01 | GSE199849 | GEO

Genome-wide characterization of MED12 occupancy in human CD34+ cells

Project description:We report ChIP-Seq data for MED12 in human CD34+ cells. Med12 occupies promoter distal regions that regulate specific transcriptional programs required for the homeostasis of the hematopoietic system. 50 milion cells were used to perform ChIP from CD34+ cells with 10 ug of antibody

2016-08-25 | E-GEOD-75914 | biostudies-arrayexpress

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