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; Mazhar Adli

doi:10.1038/s41467-023-39684-y

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, Mazhar Adli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Article number	4057
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-39684-y
State	Published - Dec 2023

Funding

We thank all members of Adli lab for their critical insights and recommendations during this study, which was supported by a pilot project award (PI: Adli) from Northwestern Uterine Leiomyoma Research Center (P50HD098580, PI: Bulun). We thank Professor Debu Chakravarti for his critical suggestion on the manuscript.

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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Buyukcelebi, K., Chen, X., Abdula, F., Elkafas, H., Duval, A. J., Ozturk, H., Seker-Polat, F., Jin, Q., Yin, P., Feng, Y., Bulun, S. E., Wei, J. J., Yue, F., & Adli, M. (2023). Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization. Nature communications, 14(1), Article 4057. https://doi.org/10.1038/s41467-023-39684-y

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

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.",

author = "Kadir Buyukcelebi and Xintong Chen and Fatih Abdula and Hoda Elkafas and Duval, {Alexander James} and Harun Ozturk and Fidan Seker-Polat and Qiushi Jin and Ping Yin and Yue Feng and Bulun, {Serdar E.} and Wei, {Jian Jun} and Feng Yue and Mazhar Adli",

note = "Funding Information: We thank all members of Adli lab for their critical insights and recommendations during this study, which was supported by a pilot project award (PI: Adli) from Northwestern Uterine Leiomyoma Research Center (P50HD098580, PI: Bulun). We thank Professor Debu Chakravarti for his critical suggestion on the manuscript. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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doi = "10.1038/s41467-023-39684-y",

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Buyukcelebi, K, Chen, X, Abdula, F, Elkafas, H, Duval, AJ, Ozturk, H, Seker-Polat, F, Jin, Q, Yin, P, Feng, Y, Bulun, SE , Wei, JJ , Yue, F & Adli, M 2023, 'Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization', Nature communications, vol. 14, no. 1, 4057. https://doi.org/10.1038/s41467-023-39684-y

TY - JOUR

T1 - Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization

AU - Buyukcelebi, Kadir

AU - Chen, Xintong

AU - Abdula, Fatih

AU - Elkafas, Hoda

AU - Duval, Alexander James

AU - Ozturk, Harun

AU - Seker-Polat, Fidan

AU - Jin, Qiushi

AU - Yin, Ping

AU - Feng, Yue

AU - Bulun, Serdar E.

AU - Wei, Jian Jun

AU - Yue, Feng

AU - Adli, Mazhar

N1 - Funding Information: We thank all members of Adli lab for their critical insights and recommendations during this study, which was supported by a pilot project award (PI: Adli) from Northwestern Uterine Leiomyoma Research Center (P50HD098580, PI: Bulun). We thank Professor Debu Chakravarti for his critical suggestion on the manuscript. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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

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