A human possesses approximately 20,000 genes. Appropriate usage of these genes generates cells with a wide variety of traits. Incorrect usage of these genes leads to various diseases, including cancer. Transcription-regulating factors interact in complex ways with many proteins, RNA, and DNA to form various structures. These structures precisely determine chromatin higher-order structures, transcription levels, splicing patterns, mRNA transport, and translation levels for each target gene. Thus, each protein molecule not only forms a uniform structure during the regulation of gene expression, but also forms, fuses, and dissociates one after another to control the enzymatic reactions that proceed with gene expression precisely. However, no method has yet been developed to spatiotemporally resolve and detect the transient multifactorial interactions organized in the cell. Therefore, we are working to elucidate the mechanism of gene expression regulated by these spatiotemporal multifactorial interactions, mainly by using novel analytical methods based on DNA barcodes (see figure).

In previous studies, we found that the novel histone methyltransferase Whsc1, identified from a database screening, functions cooperatively with the transcription factor Nkx2-5 and is the causative gene for Wolf-Hirschhorn syndrome with congenital heart disease (Nature 2009, PLoS One 2014). We found that Nkx2-5 governs chromatin structure and cooperatively terminates transcription with the transcription termination factor Xrn2 (eLife 2016). While studying in the U.S., we revealed a mechanism for rapid decondensation of chromatin structure (Mol. Cell 2017). In our research on mechanisms of gene expression regulation in cancer, we identified alternative RNA splicing regulatory mechanisms that exacerbate tumors and developed methods to control them (Cancer Res. 2019, Tetrahedron Letters 2019, ACS Medicinal Chemistry Letters 2020, Cell & Bioscience 2022). We revealed the mechanism of cancer stem cell emergence in cancer cell populations using a gene expression recording method combining DNA barcoding and Cas9/self-targeted gRNAs (Cellular and Molecular Life Sciences, 2022). Furthermore, we are working to elucidate the mechanisms of gene expression regulation that induce the antitumor effects of non-proliferative virotherapy. We are developing novel anticancer drugs based on these mechanisms of action.