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An integrative genomic and transcriptomic analysis reveals potential targets associated with cell proliferation in uterine leiomyomas

ABSTRACT: Transcriptional profiling of uterine leiomyoma tumor samples for integrative analysis with copy number alterations data. Goal was to identify up- and/or down-expressed genes associated with genomic gains and/or losses, respectively. After, it was applied to GSEA and CONEXIC algorithm to integrate the data. Protein-protein interactions also was building and the data were validated using qRT-PCR and IHC techniques.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42939 | GEO | 2012/12/16

SECONDARY ACCESSION(S): PRJNA183922

REPOSITORIES: GEO

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Project description:Purpose:Our goal was to identify and characterize a new molecular target of Bisphenol A（BPA）in uterine leiomyoma cells to better understand how this compound may affect uterine leiomyomas growth and development. Methods: Primary cultured cell lines of uterine leiomyoma were treated with 0.1% DMSO or 10.0 μmol/L BPA for 48 h before RNA-seq and histone 3 lysine 27 acetylation (H3K27ac) ChIP-seq were performed. Integrative analysis of ChIP-seq and RNA-seq data identifies the key transcription factor (TF)，target gene and signaling pathway. To confirm the expression level of TF and target gene in uterine leiomyomas tissues, we analyzed 10 human uterine leiomyoma tissues and the matched adjacent uterine smooth muscle tissues using western blotting, and 96 paired paraffin-embedded human uterine samples by immunohistochemistry(IHC). The ChIP assay used to confirm the combination between the TF and target gene. In order to verify the functions of key TF, lentivirus was used to knock down the expression level and detect the effects on cell proliferation, cell cycle, and cell tumorigenicity. We further conducted Western blot analysis to confirm the whether the downstream signaling pathway is activated. RESULTS: Integrative Analysis of ChIP-seq and RNA-seq data identifies the key transcription factor XBP1and target gene ITGA2. The qPCR and ChIP- qPCR initially verified the sequencing results. XBP1 and ITGA2 were overexpressed in human uterine leiomyoma tissues. The IHC results confirmed that ITGA2 was significantly correlated with XBP1 expression (R = 0.6708, P < 0.001)， and the ChIP assay showed that XBP1 binds to the the ITGA2 predicted promoter region. BPA promoted uterine leiomyoma cells proliferation both in vitro and in vivo and that XBP1 expression levels modulated the cellular response to this endocrine disruptor. BPA upregulated ITGA2 through XBP1 and activated the downstream PI3K-AKT signaling pathway to promote the proliferation of human uterine leiomyoma cells. CONCLUSION: In conclusion, our current work reveals a novel mechanism by which BPA promotes the proliferation in uterine leiomyoma cells. The XBP1 transcription factor regulates and activates the downstream ITGA2/PI3K/AKT pathway. By defining XBP1 as an important regulatory role of BPA in uterine leiomyoma cell proliferation, they provide new insights into the pathogenesis related to the exposure to BPA and other endocrine disruptors acting similarly, and XBP1 may serve as a candidate molecular target for intervention and treatment of uterine leiomyomas.

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An integrative genomic and transcriptomic analysis reveals potential targets associated with cell proliferation in uterine leiomyomas

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