Biology subjects

Corona, R.

Publications and source records attributed to Corona, R..

3 recordsLinked to original sources

bioRxiv2023

Rewiring of master transcription factor cistromes during high-grade serous ovarian cancer development

The transcription factors MECOM, PAX8, SOX17 and WT1 are candidate master regulators of high-grade serous ovarian cancer (HGSC), yet their cooperative role in the hypothesized tissue of origin, the fallopian tube secretory epithelium (FTSEC) is unknown. We generated 26 epigenome (CUT&TAG, CUT&RUN, ATAC-seq and HiC) data sets and 24 profiles of RNA-seq transcription factor knock-down followed by RNA sequencing in FTSEC and HGSC models to define binding sites and gene sets regulated by these factors in cis and trans. This revealed that MECOM, PAX8, SOX17 and WT1 are lineage-enriched, super-enhancer associated master regulators whose cooperative DNA-binding patterns and target genes are re-wired during tumor development. All four TFs were indispensable for HGSC clonogenicity and survival but only depletion of PAX8 and WT1 impaired FTSEC cell survival. These four TFs were pharmacologically inhibited by transcriptional inhibitors only in HGSCs but not in FTSECs. Collectively, our data highlights that tumor-specific epigenetic remodeling is tightly related to MECOM, PAX8, SOX17 and WT1 activity and these transcription factors are targetable in a tumor-specific manner through transcriptional inhibitors.

cancer biology↗

bioRxiv2023

Role of membrane estrogen receptor alpha on the positive feedback of estrogens on LH secretion

Estrogens act through nuclear and membrane-initiated signaling. Estrogen receptor alpha (ER) is critical for reproduction, but the relative contribution of its nuclear and membrane signaling is unclear. To address this question, we used two complementary approaches: estetrol (E4) a natural estrogen described to act as an agonist of nuclear ER and a mER antagonist and the C451A-ER mouse lacking mER. E4 dose-dependently blocks ovulation in female rats, but the mechanism underlying this effect is unknown. To determine whether E4 acts centrally to control ovulation, we tested its effect on the positive feedback of estradiol (E2) on LH secretion. In ovariectomized females chronically exposed to a low dose of E2, estradiol benzoate (EB) alone or combined with progesterone (P) induced a LH surge and the associated increase in the number of activated kisspeptin (Kp) and gonadotropin-releasing hormone (GnRH) neurons. However, E4 blocked these effects of EB when provided alone, but not when combined to P. These results indicate that E4 blocked the induction of the positive feedback and the associated neuronal activation in the absence of P, suggesting an antagonistic effect of E4 on mER as shown in peripheral tissues. In parallel, C451A-ER females do not show a pre-ovulatory LH surge and the associated activation of Kp and GnRH neurons in response to EB unless they are treated with P. The similarity of the responses of C451A-ER mice and wild-type females treated with E4 supports a role for membrane-initiated estrogen signaling in the EB-induced LH surge.

neuroscience↗

bioRxiv2018

Integrated Molecular Profiling Studies to Characterize the Cellular Origins of High-Grade Serous Ovarian Cancer

Historically, high-grade serous ovarian cancers (HGSOCs) were thought to arise from ovarian surface epithelial cells (OSECs) but recent data implicate fallopian tube secretory epithelial cells (FTSECs) as the major precursor. We performed transcriptomic and epigenomic profiling to characterize molecular similarities between OSECs, FTSECs and HGSOCs. Transcriptomic signatures of FTSECs were preserved in most HGSOCs reinforcing FTSECs as the predominant cell-of-origin; though an OSEC-like signature was associated with increased chemosensitivity (Padj = 0.03) and was enriched in proliferative-type tumors, suggesting a dualistic model for HGSOC origins. More super-enhancers (SEs) were shared between FTSECs and HGSOCs than between OSECS and HGSOCs (P < 2.2 x 10-16). SOX18, ELF3 and EHF transcription factors (TFs) coincided with HGSOC SEs and represent putative novel drivers of tumor development. Our integrative analyses support a predominantly fallopian origin for HGSOCs and indicate tumorigenesis may be driven by different TFs according to cell-of-origin.

cancer biology↗