GSE204969 MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma [RNA-seq]

Contributors : Azna Zuberi ; Yongchao Huang ; Ariel J Dotts ; John S Coon V ; Shimeng Liu ; Takashi Lizuka ; Yang Dai ; Ping Yin ; Priyam Patel ; Serdar E BulunSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensUterine leiomyoma (LM) is the most common tumor in women. Estrogen and progesterone, via their receptors ER α 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-dioxy genase (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, increase d 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 find...

Source: GEO: Gene Expression Omnibus - May 1, 2023 Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research