Transcription factors (TFs) play an important role in gene expression and 12their aberration is associated with various diseases. We found that a sub-group of TF can promote DNA demethylation at their own binding sites where, in most cases, their transactivation domain is associated with this activity. We also showed the importance of TF RUNX1-mediated DNA demethylation dur-ing hematopoietic differentiation.Using Familial Platelet Disorder (FPD)-mimicking hematopoietic progeni-tor cells (HPCs) with a RUNX1 mutation, we found that the expression of FLI1, an ETS family TF, was significantly downregulated. Further, we demonstrated that FLI1 promotes binding-site-directed DNA demethylation and that recov-ery of FLI1 expression in FPD-mimicking HPCs restores megakaryocytic dif-ferentiation efficiency and hypermethylation status. Using a knockout mouse of Ten-Eleven Translocation-2 (TET2), an enzyme involved in TF-mediated DNA demethylation, we used single-cell RNA sequencing and identified a novel group of progenitors that could be leukemic progenitors. These cells migrate into peripheral tissues, implying a contribution to the pathogenesis of leukemia and its associated diseases.We also employed Visium spatial transcriptome analysis to explore the ex-pression dynamics of MYCN, a basic helix-loop-helix TF, in hepatocellular car-cinoma. MYCN was highly expressed at the tissue region where developmental signaling pathways, such as Wnt/β-catenin signaling, were enriched. Further, we observed that mice with combined overexpression of MYCN and myristoylated AKT displayed a 72% incidence of liver cancer (Figure), strongly suggesting a functional role of MYCN in the oncogenic transformation of hepatocytes.In the epithelial-to-mesenchymal transition (EMT), we also found that cells at the center of epithelial colonies are resistant to EMT and that proteasomal degradation of TF ZEB1 protein, mediated by the CDK4/6-USP51 pathway, is in-volved in this process. In intestinal regeneration, we examined whether toll-like receptor (TLR) pathways in immune cells are involved in stem cell regeneration and found that they are rather important for maintaining intestinal stem cells.Figure: lmmunofluorescence staining of a mouse liver section with overexpression of MYCN (Green) and myristoylated AKT (Red)The hepatic progenitor/bile duct marker pan-cytokeratin is shown in white and nuclei are shown in blue (DAPI).Recent Major PublicationsFurutani Y, Hirano Y, Toguchi M, Higuchi S, Qin XY, Yanaka K, Sato-Shiozaki Y, Takahashi N, Sakai M, Kongpracha P, Suzuki T, Dohmae N, Kukimoto-Niino M, Shirouzu M, Nagamori S, Suzuki H, Kobayashi K, Masaki T, Koyama H, Sekiba K, Otsuka M, Koike K, Kohara M, Kojima S, Kakeya H, Matsuura T. A small molecule iCDM-34 identified by in silico screening suppresses HBV DNA through activa-tion of aryl hydrocarbon receptor. Cell Death Discov 2023, 9(1): 467Qin XY, Furutani Y, Yonezawa K, Shimizu N, Kato-Murayama M, Shirouzu M, Xu Y, Yamano Y, Wada A, Gail-houste L, Shrestha R, Takahashi M, Keillor JW, Su T, Yu W, Fujii S, Kagechika H, Dohmae N, Shirakami Y, Shimizu M, Masaki T, Matsuura T, Suzuki H, Kojima S. Targeting transglutaminase 2 mediated exostosin glycosyltrans-ferase 1 signaling in liver cancer stem cells with acyclic retinoid. Cell Death Dis 2023, 14(6): 358Invited presentationsQin XY. “Clinical significance of serum MYCN in the prediction of liver cancer treatment and prognosis” The 63rd Annual Meeting of the Japan Society of Clinical Chemistry, Symposium: Biomarker Research in Liver Disease (Tokyo, Japan) October 2023Qin XY, Furutani Y, Matsuura T, Suzuki H. “Spatial omics analysis of tumor promoting microenvironment and retinoic acid signal dynamics in NASH-induced liver tumorigenesis” The 377th Research Committee of Fat Soluble Vitamins (Tokyo, Japan) September 2023Qin XY. “Identification of and drug discovery targeting a novel liver cancer stem cell marker MYCN” The 887th Research Meeting of Chiba Cancer Center Research Insti-tute (Chiba, Japan) August 2023Laboratory for Cellular Function Conversion TechnologyTeam Leader: Harukazu Suzuki
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