Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization.
Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization.
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工程化的 MED12 突变通过改变 3D 基因组区室化来驱动类似平滑肌瘤的转录和代谢程序。
DOI：
10.1038/s41467-023-39684-y
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发表时间：
2023-07-10
影响因子：
16.6
通讯作者：
Adli, Mazhar
中科院分区：
文献类型：
--
作者：
Buyukcelebi, Kadir;Chen, Xintong;Abdula, Fatih;Elkafas, Hoda;Duval, Alexander James;Ozturk, Harun;Seker-Polat, Fidan;Jin, Qiushi;Yin, Ping;Feng, Yue;Bulun, Serdar E.;Wei, Jian Jun;Yue, Feng;Adli, Mazhar
近70%的子宫肌瘤（UF）是由复发性MED12热点突变驱动的。不幸的是，由于突变细胞在二维培养条件下适应度较低，无法生成细胞模型。为了解决这个问题，我们使用CRISPR精确地在uf相关的肌平滑肌细胞中设计MED12 Gly44突变。基因工程的突变细胞重现了几种类似uf的细胞、转录和代谢改变，包括色氨酸/犬尿氨酸代谢的改变。突变细胞中的异常基因表达程序部分是由大量的3D基因组区隔化开关驱动的。在细胞水平上，突变细胞在三维球体中的增殖率增强，在体内形成更大的病变，胶原蛋白和细胞外基质沉积增加。这些发现表明，工程细胞模型忠实地模拟了UF肿瘤的关键特征，并为更广泛的科学界表征复发性MED12突变的基因组学提供了一个平台。目前缺乏研究子宫肌瘤（UFs）肿瘤生物学的遗传模型。在这里，作者精确地设计了带有MED12 Gly-44突变体的细胞，并产生了肌层平滑肌细胞（SMCs），再现了主要的ufs样细胞、转录和代谢改变。
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. There are currently a lack of genetic models to study the biology of Uterine fibroids (UFs) tumours. Here the authors precisely engineer cells with mutant MED12 Gly-44 and generate myometrial smooth muscle cells (SMCs) that recapitulate major UFs-like cellular, transcriptional, and metabolic alterations.
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影响因子：
14.9
作者：
Brinkman, Eva K.;Kousholt, Arne N.;van Steensel, Bas
通讯作者：
van Steensel, Bas
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
64.5
作者：
El Khattabi L;Zhao H;Kalchschmidt J;Young N;Jung S;Van Blerkom P;Kieffer-Kwon P;Kieffer-Kwon KR;Park S;Wang X;Krebs J;Tripathi S;Sakabe N;Sobreira DR;Huang SC;Rao SSP;Pruett N;Chauss D;Sadler E;Lopez A;Nóbrega MA;Aiden EL;Asturias FJ;Casellas R
通讯作者：
Casellas R
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.5
作者：
Dekker J;Mirny L
通讯作者：
Mirny L