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Next-Generation Sequencing Facilitates Quantitative Analysis of Control and BET bromodomain Inhibitor-treated Uterine fibroids Cell Transcriptome

ABSTRACT: We report that BET bromodomain inhibition alters multiple biological pathways in uterine fibroid cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE281309 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Uterine fibroids are benign tumours affecting up to 80% of women of reproductive age, with 30% of patients suffering severe symptoms including abnormal uterine bleeding, pain and infertility. Several studies have identified mutations in MED12 or HMGA2 that account for the vast majority of genomic abnormalities in uterine fibroids, however, the processes by which these lead to UFs and HMB remain poorly understood. To systematically correlate genetic, transcriptional and proteomic phenotypes we collected fibroid, myometrium and endometrium tissues from 137 donors undergoing hysterectomy, myomectomy, or transcervical resection. Donors were profiled by genome-wide SNP arrays and their fibroids were genotyped for known mutations using a targeted sequencing approach. Tissues were analysed by RNA-sequencing and proteomics followed by a systems level approach using multiomics factor analysis. Whilst genotyping revealed 39.7% of common MED12 UF mutations, we observe multiple novel exonic and intronic variants of previously known mutated genes like COL4A5 and COL4A6. Systems level analysis of genotype, transcriptomic, and proteomic data between myometrium and fibroid donors identified multiple interrelated gene sets involved in UF pathophysiology, including extracellular matrix deposition and remodelling, protein glycosylation and sulphate biology. Equivalent analysis of endometrium stratified by donor HMB status revealed gene sets implicated in the condition, in particular RNA splicing in MED12 mutant fibroids. A paradigm is proposed, supported by a mouse model of HMB, whereby aberrant production of signalling molecules by MED12 mutant fibroids influences RNA transcript isoform expression in the endometrium, associated with abnormal bleeding. By merging clinical, genetic, transcriptomic, and proteomic information, we highlight multiple pathways which may underlie the pathomechanisms of UF biology and may facilitate the development of novel therapeutic strategies to treat heavy menstrual bleeding

Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. JQ1 is a novel thieno-triazolo-1,4-diazepine, which displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket. BE(2)-C and Kelly cells were treated in triplicate with 1 ÂµM JQ1 or DMSO for 24 hours. RNA was extracted and a decrease in MYCN transcript was confirmed by real time RT-PCR as described above. The samples were profiled using the Affymetrix PrimeView Human Gene Expression Array (Affymetrix) at Beth Israel Deaconess Medical Center (Boston, MA, USA).

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Next-Generation Sequencing Facilitates Quantitative Analysis of Control and BET bromodomain Inhibitor-treated Uterine fibroids Cell Transcriptome

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