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

Reviewer #1 (Public Review):

This manuscript describes extensive transcriptomic and epigenomic profiling for high-grade serous 'ovarian' cancer (HGSC) and its precancerous precursor the fallopian tube secretory epithelium cells (FTSEC). This study identifies MECOM, PAX8, SOX17 and WT1 as master transcription factors that regulate HGSC and FTSEC, as well as the transition from FTSEC to HGSC.

Overall, most the experiments described in the manuscript are well designed and executed. The data presented are of high quality, convincing, and in general support the conclusions made in the manuscript.

Given the complexity of the data and analysis, some clarification is needed to guide readers to better understand the results.

1. The definition of super enhancers should be clarified. In general, super enhancers are defined by large domains of enhancer clusters with high levels of H3K27ac, typically at least 10KB in size. The "super enhancers" presented in Figure 2 do not appear to be large clusters of enhancers.

2. Fig. 4D. Difficult to understand. Multiple bars seem to be represented by the same binding patterns by the four TFs. Need better description in both the text and figure legends.

3. "These data suggest that the antiproliferative effects of THZ1 and THZ531 in HGSC cells may be due to tumor-specific inhibition of MECOM, PAX8 and SOX17 expression by these drugs." Can the author expand the discussion on how CDK7/12 inhibitors could achieve tumor-specific inhibition of MECOM, PAX8 and SOX17?

Reviewer #2 (Public Review):

This study found that MECOM, PAX8, SOX17, and WT1, as the main regulators of high-grade serous ovarian cancer (HGSC), their transcriptional regulation related to the super-enhancer, were reconnected in the process of tumor development. These four TFS are essential for the clonality and survival of HGSC, while the absence of PAX8 and WT1 in non-cancerous fallopian tube secretory epithelium (FTSEC) can impair the survival of cells. These four TFS are only pharmacologically inhibited by transcriptional inhibitors in HGSCs, while not in FTSECs, making them potential targets for tumor-specific therapy.

I am thrilled to see such an exciting and scientific manuscript. The results will significantly impact the basic theory of cancer occurrence and clinical applications.

However, there were some issues with the data presentation. We hope that the author will carefully and rigorously review the data and visualization results. In addition, there is key information missing in the methods section, which does not meet the current requirements for the repeatability of scientific conclusions.