Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization
Nearly 70% of Uterine fibroid (UF) tumors are driven by recurrent MED12 hotspot mutations.
Unfortunately, no cellular models could be generated because the mutant cells have lower
fitness in 2D culture conditions. To address this, we employ CRISPR to precisely engineer
MED12 Gly44 mutations in UF-relevant myometrial smooth muscle cells. The engineered
mutant cells recapitulate several UF-like cellular, transcriptional, and metabolic alterations,
including altered Tryptophan/kynurenine metabolism. The aberrant gene expression …
Unfortunately, no cellular models could be generated because the mutant cells have lower
fitness in 2D culture conditions. To address this, we employ CRISPR to precisely engineer
MED12 Gly44 mutations in UF-relevant myometrial smooth muscle cells. The engineered
mutant cells recapitulate several UF-like cellular, transcriptional, and metabolic alterations,
including altered Tryptophan/kynurenine metabolism. The aberrant gene expression …
[HTML][HTML] Engineered MED12 mutations drive uterine fibroid-like transcriptional and metabolic programs by altering the 3D genome compartmentalization
K Buyukcelebi, X Chen, F Abdula, A Duval… - Research …, 2023 - ncbi.nlm.nih.gov
Uterine fibroid (UF) tumors originate from a mutated smooth muscle cell (SMC). Nearly 70%
of these tumors are driven by hotspot recurrent somatic mutations in the MED12 gene;
however, there are no tractable genetic models to study the biology of UF tumors because,
under culture conditions, the non-mutant fibroblasts outgrow the mutant SMC cells, resulting
in the conversion of the population to WT phenotype. The lack of faithful cellular models
hampered our ability to delineate the molecular pathways downstream of MED12 mutations …
of these tumors are driven by hotspot recurrent somatic mutations in the MED12 gene;
however, there are no tractable genetic models to study the biology of UF tumors because,
under culture conditions, the non-mutant fibroblasts outgrow the mutant SMC cells, resulting
in the conversion of the population to WT phenotype. The lack of faithful cellular models
hampered our ability to delineate the molecular pathways downstream of MED12 mutations …
