Panax ginseng
, known as Koran ginseng, one of the most commonly used traditional plants, has been demonstrated to show a wide range of pharmacological applications. Ginsenosides are the major active ingredients found in ginseng and are responsible for the biological and pharmacological activities, such as antioxidation, antiinflammation, vasorelaxation, and anticancer actions. Existing studies have mostly focused on identifying and purifying single ginsenosides and investigating pharmacological activities and molecular mechanisms in cells and animal models. However, ginsenoside studies based on clinical trials have been very limited. Therefore, this review aimed to discuss the currently available clinical trials on ginsenosides and provide insights and future directions for developing ginsenosides as efficacious and safe drugs for human disease.
Although several studies have suggested that the functions of heterochromatin regulators may be regulated by post-translational modifications during cell cycle progression, regulation of the histone methyltransferase Suv39H1 is not fully understood. Here, we demonstrate a direct link between Suv39H1 phosphorylation and cell cycle progression. We show that CDK2 phosphorylates Suv39H1 at Ser391 and these phosphorylation levels oscillate during the cell cycle, peaking at S phase and maintained during S-G2-M phase. The CDK2-mediated phosphorylation of Suv39H1 at Ser391 results in preferential dissociation from chromatin. Furthermore, phosphorylation-mediated dissociation of Suv39H1 from chromatin causes an enhanced occupancy of JMJD2A histone demethylase on heterochromatin and alterations in inactive histone marks. Overexpression of phospho-mimic Suv39H1 induces early replication of heterochromatin, suggesting the importance of Suv39H1 phosphorylation in the replication of heterochromatin. Moreover, overexpression of phospho-defective Suv39H1 caused altered replication timing of heterochromatin and increases sensitivity to replication stress. Collectively, our data suggest that phosphorylation-mediated modulation of Suv39H1-chromatin association may be an initial step in heterochromatin replication.
To escape the immune system, tumor cells may remove surface molecules such as the major histocompatibility complex (MHC) and co-stimulatory molecules, which are essential for recognition by lymphocytes. Down-regulation of the co-stimulatory molecules CD70 (TNFSF7) and CD80 may contribute to tumor cell survival; however, the mechanism of down-regulation of the TNFSF7 gene during tumorigenesis is poorly understood. Here we present evidence indicating that TNFSF7 gene expression is epigenetically down-regulated via DNA hypermethylation within its promoter region during progression in breast cancer cells in the isogenic MCF10 model. Bisulfite sequencing revealed that the CpG pairs at the proximal region of the TNFSF7 promoter are heavily methylated during progression of breast cancer cells but that methylation of the more distal sequences was not changed considerably. Thus, this epigenetic silencing of the TNFSF7 gene via hypermethylation of its proximal region may allow the benign and invasive MCF10 variants to escape immune surveillance.
Primordial germ cell (PGC) specification is one of the most fundamental processes in developmental biology. Because PGCs are a common source of both gametes, generation of PGCs from embryonic stem cells (ESCs) is a useful model for analysing the germ line lineage. Although several studies focused on the role of epigenetic regulation on PGC differentiation from ESCs in vitro have been published, germ line commitment remains poorly understood. Here, we show that SET domain-containing protein (Setd5), which has a previously unknown function, is essential for regulating germ cell-associated genes in murine ESCs (mESCs). Even though Setd5 knockdown with 3 distinct shRNAs did not affect expression of pluripotency genes or levels of global histone methylation, all 3 shRNAs significantly diminished the expression of early and late-stage PGC-associated genes. Furthermore, our immunoprecipitation assay showed that Setd5 can interact with Tbl1xr1 and Ctr9, which are components of 2 different transcriptional regulatory complexes, namely, NcoR1 corepressor complex and Paf1 complex, respectively, in mESCs. Taken together, our data suggest that Setd5 is required for maintaining PGC-associated genes and Setd5-associated protein complexes containing Tbl1xr1 and Ctr9, which in turn are likely involved in regulating germ cell-related genes in mESCs.
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