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

Kadir Buyukcelebi, Xintong Chen, Fatih Abdula, Hoda Elkafas, Alexander James Duval, Harun Ozturk, Fidan Seker-Polat, Qiushi Jin, Ping Yin, Yue Feng, Serdar E. Bulun, Jian Jun Wei, Feng Yue and Mazhar Adli ()
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Kadir Buyukcelebi: Feinberg School of Medicine at Northwestern University
Xintong Chen: Feinberg School of Medicine Northwestern University
Fatih Abdula: Feinberg School of Medicine at Northwestern University
Hoda Elkafas: Feinberg School of Medicine at Northwestern University
Alexander James Duval: Feinberg School of Medicine at Northwestern University
Harun Ozturk: Feinberg School of Medicine at Northwestern University
Fidan Seker-Polat: Feinberg School of Medicine at Northwestern University
Qiushi Jin: Feinberg School of Medicine Northwestern University
Ping Yin: Feinberg School of Medicine at Northwestern University
Yue Feng: Northwestern University Feinberg School of Medicine
Serdar E. Bulun: Feinberg School of Medicine at Northwestern University
Jian Jun Wei: Feinberg School of Medicine at Northwestern University
Feng Yue: Feinberg School of Medicine Northwestern University
Mazhar Adli: Feinberg School of Medicine at Northwestern University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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 program in the mutant cells is, in part, driven by a substantial 3D genome compartmentalization switch. At the cellular level, the mutant cells gain enhanced proliferation rates in 3D spheres and form larger lesions in vivo with elevated production of collagen and extracellular matrix deposition. These findings indicate that the engineered cellular model faithfully models key features of UF tumors and provides a platform for the broader scientific community to characterize genomics of recurrent MED12 mutations.

Date: 2023
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DOI: 10.1038/s41467-023-39684-y

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