The role of mediator complex subunit 12 (MED12) in the murine reproductive tract

Uterine leiomyomas are benign neoplasms arising from smooth muscle cells of the uterus. They are clinically diagnosed in 25% of women and are associated with significant morbidity. Whole exome approaches have identified heterozygous somatic mutations in the mediator complex subunit 12 (MED12) in about 70% of leiomyomas with a majority harboring in exon 2 of MED12 with c.131G>A being the most common SNV. MED12 protein is part of the large mediator complex and is involved in transcriptional regulation of RNA Polymerase II. To elucidate the role of MED12 exon 2 variants in leiomyomagenesis, we generated three different mouse models of Med12; loss-of-function, dominant-negative and gain-of-function mouse models. \ud The loss-of-function females lacked any leiomyoma-like lesions, instead the reproductive tracts were hypoplastic and the females were infertile. \ud We engineered a model where we conditionally floxed Med12 c.131G>A cDNA and inserted into the ROSA26 locus to generate Med12 ROSA knock-in mice. Amhr2-cre was used to drive the expression of the mutant Med12 from the ROSA locus either in the absence (gain-of-function) or presence (dominant-negative) of X-chromosome wild-type Med12 in the uterine mesenchyme. Uteri from (gain-of-function) females displayed leiomyoma-like lesions in about 87% of females. Similar characterization of uteri of dominant negative females revealed the development of leiomyoma-like lesions, but with appearance of smaller lesions and lower penetrance (50% of females) as compared to the gain-of-function model, leading us to conclude that the Med12 exon 2 variants are likely to cause uterine leiomyomas via gain-of-function mechanism. \ud Array comparative genomic hybridization (aCGH) of mouse tumors displayed genome wide aberrations, affecting general tumor pathways. Interestingly, several regions previously implicated in human leiomyomas were also shared by the mouse leiomyomas, revealing the similarities between human and mouse leiomyomas. This data suggests that Med12 exon 2 mutations are precursors to genomic rearrangements leading to an unstable genome. The public health significance of this work includes the successful development of the first animal model for uterine leiomyomas, which will be an invaluable tool to understand the role of MED12 in leiomyoma genesis, as well as provide a unique platform to test targeted therapeutics as an alternative to hysterectomies.\u