Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Bromodomain Containing 9 Regulates Signaling Pathways and Reprograms the Epigenome in Human Uterine Fibroid Cells

Qiwei Yang
* ORCID logo ,
Somayeh Vafaei
,
Ali Falahati
,
Azad Khosh
,
Maria Victoria Bariani
ORCID logo ,
Mervat M Omran
,
Tao Bai
,
Hiba Siblini
,
Mohamed Ali
,
Chuan He
,
Thomas G Boyer
,
Ayman Al-Hendy
ORCID logo
Version 1 : Received: 15 July 2023 / Approved: 17 July 2023 / Online: 18 July 2023 (04:30:08 CEST)

How to cite: Yang, Q.; Vafaei, S.; Falahati, A.; Khosh, A.; Bariani, M.V.; Omran, M.M.; Bai, T.; Siblini, H.; Ali, M.; He, C.; Boyer, T.G.; Al-Hendy, A. Bromodomain Containing 9 Regulates Signaling Pathways and Reprograms the Epigenome in Human Uterine Fibroid Cells. Preprints 2023, 2023071154. https://doi.org/10.20944/preprints202307.1154.v1 Yang, Q.; Vafaei, S.; Falahati, A.; Khosh, A.; Bariani, M.V.; Omran, M.M.; Bai, T.; Siblini, H.; Ali, M.; He, C.; Boyer, T.G.; Al-Hendy, A. Bromodomain Containing 9 Regulates Signaling Pathways and Reprograms the Epigenome in Human Uterine Fibroid Cells. Preprints 2023, 2023071154. https://doi.org/10.20944/preprints202307.1154.v1

Abstract

Bromodomain (BRD)-containing proteins are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD protein dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRD proteins in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 protein in UFs and matching myometrium and further assess the impact of BRD9 inhibitors on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD protein expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor I-BRD9. Targeted inhibition of BRD9 suppressed the UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways, reprogrammed the UF cell epigenome and epitranscriptome, and altered miRNA-mediated gene regulation in UFs. Taken together, our data support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRD proteins might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.

Keywords

Uterine fibroids; BRD9 inhibitors; Cell proliferation; Extracellular Matrix; Transcriptome; Epigenome; m6A regulators; Epitranscriptome

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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