2_PAMU840036036DNA methylation is an important epigenetic modification to regulate 12E12.5 Ovarian Somatic CellsFetal Ovarian Somatic Cell–Like Cells−4−8−6−3−6UMAP_1−3mammalian gene expression. In order to explore transcription factors (TFs) associated with DNA methylation changes, we validated a subset of the bioinformatically selected TFs using an in vitro assay and found that 28 of 49 TFs from various TF families had DNA-demethylation-promoting activity. In sex determination of gonads at E10.5-12.5, Nr5a1 and Gata4 were suggested to regulate DNA demethylation. Furthermore, we confirmed that the RUNX1 TF is essential for differentiation from iPS cells to pre-HSPC II cells (CD44High cKitNeg). Moreover, this differentiation was significantly reduced by a RUNX1 mutant lacking DNA-demethylation-promoting activity, suggesting the impor-tance of RUNX1-mediated DNA demethylation in hematopoietic differentiation.We also analyzed disorders associated with aberrant DNA methylation. Ten-Eleven Translocation-2 (Tet2) is one of the most commonly mutated genes in myeloproliferative neoplasms (MPN). Using single-cell RNA sequencing analy-sis of progenitors isolated from hematopoietic cell-specific Tet2-deficient mice, we identified a novel group of progenitors that may contribute to MPN patho-genesis. In familial platelet disorder (FPD), we found abnormalities of DNA methylation related to platelet functions in hematopoietic progenitor cells with FPD mutations, suggesting that DNA methylation abnormalities are involved in FPD pathology. Furthermore, we have begun the analysis of the “second-hit” (second mutation) for tumor genesis in FPD and an epigenetic biomarker search for endometrial cancer.We analyzed the generation of ovarian follicles from mouse pluripotent stem cells using single-cell RNA sequencing (Figure). This technology was also applied to in vitro organ cultured testes to analyze the global inflammatory response.Using large-scale CRISPR-Cas9 screening, we identified several potential epigenetic regulators including MEN1 during epithelial-to-mesenchymal tran-sition (EMT). Furthermore, we found that EMT preferentially occurred at the peripheral edge of solid tumors, where proteasomal regulation of the ZEB1 TF was suggested to play an important role in this process.Figure: UMAP projection showed similar pattern between ovar-ian somatic-like cells generated from pluripotent stem cells (right) and E12.5 ovarian somatic cells (left). Each color represents cell clusters.Recent Major PublicationsYoshino T, Suzuki T, Nagamatsu G, Yabukami H, Ikegaya M, Kishima M, Kita H, Imamura T, Nakashima K, Nishi-nakamura R, Tachibana M, Inoue M, Shima Y, Morohashi K, Hayashi K. Generation of ovarian follicles from mouse pluripotent stem cells. Science 373, eabe0237 (2021)Suzuki T, Abe T, Ikegaya M, Suzuki K, Yabukami H, Sato T, Komeya M, Ogawa T. Global inflamma-tory response in in vitro organ cultured testes using single-cell RNA-sequencing. bioRxiv https://doi.org/10.1101/2021.12.01.470873 (2021)Ozturk M, Chia JE, Hazra R, Saqib M, Maine RA, Guler R, Suzuki H, Mishra BB, Brombacher F, Parihar SP. Evalua-tion of Berberine as an Adjunct to TB Treatment. Front Immunol 12, 656419 (2021)Laboratory for Cellular Function Conversion TechnologyTeam Leader: Harukazu Suzuki
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