An integrated genomic approach identifies HOXC8 as an upstream regulator in ovarian endometrioma

Ryo Maekawa, Mihara, Yumiko, Shun Sato, Shimizu, Natsuko, Doi-Tanaka, Yumiko, Takagi, Haruka, Yuichiro Shirafuta, Shinagawa, Masahiro, Isao Tamura, Taketani, Toshiaki, Tamura, Hiroshi, Abe, Takeshi, Asai, Yoshiyuki, Sugino, Norihiro
2020 · doi:10.5061/dryad.s4mw6m94g · W6967125047
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This study integrated genomic data and network simulations to identify HOXC8 as an upstream regulator in ovarian endometrioma, demonstrating its role in promoting pathological features via TGF-ß signaling.

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This study utilized the SMITE method to identify upstream regulators of ovarian endometrioma by analyzing transcriptome data from stromal cells alongside public gene regulatory networks. The researchers confirmed that HOXC8 is overexpressed in these lesions and demonstrated through Boolean simulation that its aberrant expression drives pathological features such as proliferation, migration, and fibrosis. Experimental validation showed that HOXC8 overexpression activates TGF-ß signaling, a process that can be inhibited by specific kinase inhibitors, thereby linking this transcription factor directly to the disease mechanism. This paper is centrally about endometriosis — specifically investigating the molecular pathogenesis of ovarian endometrioma lesions.

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Abstract

Purpose: To identify the upstream regulators (URs) involved in the onset and pathogenesis of ovarian endometrioma. Methods: Recently, a method called SMITE that uses transcriptome data in combination with publicly available data for identifying URs of cellular processes has been developed. Here, we used SMITE with transcriptome data from ovarian endometrioma stromal cells (ovESCs) and eutopic endometrium stromal cells (euESCs) in combination with publicly available gene regulatory network data. To confirm the URs identified by SMITE, we developed a Boolean network simulation to see if correcting aberrant expressions of the identified genes could restore the entire gene expression profile of ovESCs to a profile similar to that of euESCs. We then established euESCs overexpressing the identified gene and characterized them by cell function assays and transcriptome analysis. Results: SMITE identified 12 potential URs in ovarian endometrioma that were confirmed by the Boolean simulation. One of the URs, HOXC8, was confirmed to be overexpressed in ovESCs. HOXC8 overexpression significantly enhanced cell proliferation, migration, adhesion, and fibrotic activities, and altered expression statuses of the genes involved in TGF-ß signaling. HOXC8 overexpression also increased the expression levels of phosphorylated SMAD2/SMAD3. The increased adhesion and fibrosis activities by HOXC8 were significantly inhibited by E-616452, a selective inhibitor of TGF-ß receptor type I kinases. Main Conclusions: Integrated genomic approaches identified HOXC8 as an UR in ovarian endometrioma. The pathological features of ovarian endometrioma including cell proliferation, adhesion, and fibrosis were induced by HOXC8 and its subsequent activation of TGF-ß signaling.
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Abstract

Purpose: To identify the upstream regulators (URs) involved in the onset and pathogenesis of ovarian endometrioma.

Methods

Recently, a method called SMITE that uses transcriptome data in combination with publicly available data for identifying URs of cellular processes has been developed. Here, we used SMITE with transcriptome data from ovarian endometrioma stromal cells (ovESCs) and eutopic endometrium stromal cells (euESCs) in combination with publicly available gene regulatory network data. To confirm the URs identified by SMITE, we developed a Boolean network simulation to see if correcting aberrant expressions of the identified genes could restore the entire gene expression profile of ovESCs to a profile similar to that of euESCs. We then established euESCs overexpressing the identified gene and characterized them by cell function assays and transcriptome analysis.

Results

SMITE identified 12 potential URs in ovarian endometrioma that were confirmed by the Boolean simulation. One of the URs, HOXC8, was confirmed to be overexpressed in ovESCs. HOXC8 overexpression significantly enhanced cell proliferation, migration, adhesion, and fibrotic activities, and altered expression statuses of the genes involved in TGF-ß signaling. HOXC8 overexpression also increased the expression levels of phosphorylated SMAD2/SMAD3. The increased adhesion and fibrosis activities by HOXC8 were significantly inhibited by E-616452, a selective inhibitor of TGF-ß receptor type I kinases. Main Conclusions: Integrated genomic approaches identified HOXC8 as an UR in ovarian endometrioma. The pathological features of ovarian endometrioma including cell proliferation, adhesion, and fibrosis were induced by HOXC8 and its subsequent activation of TGF-ß signaling. - Mihara, Yumiko et al. (2020), An Integrated Genomic Approach Identifies HOXC8 as an Upstream Regulator in Ovarian Endometrioma, The Journal of Clinical Endocrinology & Metabolism, Journal-article, https://doi.org/10.1210/clinem/dgaa618

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