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

Buyukcelebi, Kadir; Chen, Xintong; Abdula, Fatih; Elkafas, Hoda; Duval, Alexander James; Öztürk, Harun; Seker-Polat, Fidan; Jin, Qiushi; Yin, Ping; Bulun, Serdar E.; Wei, Jian‐Jun; Yue, Feng; Adli, Mazhar

doi:10.1038/s41467-023-39684-y

Cited by 6 publications

(8 citation statements)

References 86 publications

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“…However, the precise mechanism behind this heightened adaptability in a 3D culture context has yet to be elucidated. A recent study about MED12 Gly-44 mutations in the context of leiomyoma revealed findings in line with our results (67). While MED12 Gly-44 mutant cells displayed a proliferation deficiency under 2D culture conditions, these mutants formed notably larger spheroids in 3D spheroid environments compared to wild-type cells.…”

Section: Discussionsupporting

confidence: 93%

Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling

Bae,

Chen,

Chen

et al. 2023

Preprint

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Breast cancer metastatic relapse after a latency period, known as metastatic dormancy. Through genetic screening in mice, we identified the mediator complex subunit 4 (Med4) as a novel tumor-cell intrinsic gatekeeper in metastatic reactivation.Med4downregulation effectively awakened dormant breast cancer cells, prompting macroscopic metastatic outgrowth in the lungs.Med4depletion results in profound changes in nuclear size and three-dimensional chromatin architecture from compacted to relaxed states in contrast to the canonical function of the Mediator complex. These changes rewire the expression of extracellular matrix proteins, integrins, and signaling components resulting in integrin-mediated mechano-transduction and activation of YAP and MRTF. The assembly of stress fibers pulls on the nuclear membrane and contributes to reinforcing the overall chromatin modifications byMed4depletion. MED4 gene deletions were observed in patients with metastatic breast cancer, and reducedMED4expression correlates with worse prognosis, highlighting its significance as a potential biomarker for recurrence.Significance: This work establishes the first link between Med4 and its role as an epigenetic and transcriptional repressor of ECM programs that reactivates dormant tumor cells in breast cancer metastasis. We highlight the distinct noncanonical role of Med4, in contrast to Med1, as well as the functional implicationsin vitroandin vivo. We have functionally validated the aberrant signaling pathways activated through both genetic add back and chemical inhibition and correlate our findings with Med4 expression, metastatic potential, and overall outcome in retrospective patient cohorts.

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Section: Discussionsupporting

confidence: 93%

Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling

Bae,

Chen,

Chen

et al. 2023

Preprint

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“…The single-cell data also allows for examining how the overall tissue architecture and cellular composition change between a normal and disease state. Critically, in line with known disease pathology 1 , 38 , we noted a drastic increase in the percentage of SMC cells in UF tumors (from ~14% in myometrium to ~65% in Fibroids) (Fig. 3b ).…”

Section: Resultssupporting

confidence: 85%

Integrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types

Buyukcelebi,

Duval,

Abdula

et al. 2024

Nat Commun

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Uterine fibroids (UF), that can disrupt normal uterine function and cause significant physical and psychological health problems, are observed in nearly 70% of women of reproductive age. Although heritable genetics is a significant risk factor, specific genetic variations and gene targets causally associated with UF are poorly understood. Here, we performed a meta-analysis on existing fibroid genome-wide association studies (GWAS) and integrated the identified risk loci and potentially causal single nucleotide polymorphisms (SNPs) with epigenomics, transcriptomics, 3D chromatin organization from diverse cell types as well as primary UF patient’s samples. This integrative analysis identifies 24 UF-associated risk loci that potentially target 394 genes, of which 168 are differentially expressed in UF tumors. Critically, integrating this data with single-cell gene expression data from UF patients reveales the causal cell types with aberrant expression of these target genes. Lastly, CRISPR-based epigenetic repression (dCas9-KRAB) or activation (dCas9-p300) in a UF disease-relevant cell type further refines and narrows down the potential gene targets. Our findings and the methodological approach indicate the effectiveness of integrating multi-omics data with locus-specific epigenetic editing approaches for identifying gene- and celt type-targets of disease-relevant risk loci.

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“…This mutation differs from most of the previously reported MED12 mutations, which predominantly occur in exon 2 and intron 1 ( 22 , 23 ). MED12 is a constituent of the mediator complex, which acts as a key regulatory factor for the transcription of numerous genes ( 24 , 25 ). Somatic mutations in MED12 have been identified in approximately 70% of uterine leiomyomas and 10% of leiomyosarcomas ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Intravenous metastasis of unexpected uterine sarcoma in the context of uterine fibroids: case report and literature review

Huang,

Zhang,

Wang

et al. 2024

Front. Oncol.

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ObjectiveEndometrial stromal tumors are rare and complex mesenchymal tumors that often present with clinical symptoms similar to uterine leiomyomas. Due to their atypical nature, they are prone to be misdiagnosed or overlooked by healthcare professionals. This study presents a case report of an incidentally discovered endometrial stromal sarcoma with venous metastasis, which was initially misdiagnosed as a uterine leiomyoma. In addition, this study reviews previously documented cases of similar tumors.Case reportDuring a routine medical examination in 2016, a 50-year-old woman was diagnosed with uterine fibroids. In June 2020, she began experiencing moderate, irregular vaginal bleeding. Nevertheless, a histopathological examination indicated an endometrial stromal sarcoma with a striking amalgamation of both low-grade and high-grade features. Molecular analysis identified a rare MED12 gene mutation. The patient underwent total hysterectomy, bilateral salpingectomy, and resection of the metastatic lesions. Postoperative management included radiotherapy, chemotherapy, and hormone therapy. After completion of chemotherapy, the patient was followed up for 27 months with no evidence of tumor recurrence.ConclusionThis case report highlights the importance of pathological, immunohistochemical, and molecular aspects of this rare tumor involving the inferior vena cava and showing the presence of atypical gene mutations. The successful treatment outcome further emphasizes the importance of advances in diagnostic modalities for managing rare tumors like this.

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

Cited by 6 publications

References 86 publications

Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling

Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling

Integrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types

Intravenous metastasis of unexpected uterine sarcoma in the context of uterine fibroids: case report and literature review

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