The processes of DNA replication and mitosis allow the genetic information of a cell to be copied and transferred reliably to its daughter cells. However, if DNA replication and cell division were always carried out in a symmetric manner, it would result in a cluster of tumor cells instead of a multicellular organism. Therefore, gaining a complete understanding of any complex living organism depends on learning how cells become different while faithfully maintaining the same genetic material. It is well recognized that the distinct epigenetic information contained in each cell type defines its unique gene expression program. Nevertheless, how epigenetic information contained in the parental cell is either maintained or changed in the daughter cells remains largely unknown. During the asymmetric cell division (ACD) of Drosophila male germline stem cells (GSCs), our previous work revealed that preexisting histones are selectively retained in the renewed stem cell daughter, whereas newly synthesized histones are enriched in the differentiating daughter cell. We also found that randomized inheritance of preexisting histones versus newly synthesized histones results in both stem cell loss and progenitor germ cell tumor phenotypes, suggesting that programmed histone inheritance is a key epigenetic player for cells to either remember or reset cell fates. Here we will discuss these findings in the context of current knowledge on DNA replication, polarized mitotic machinery, and ACD for both animal development and tissue homeostasis. We will also speculate on some potential mechanisms underlying asymmetric histone inheritance, which may be used in other biological events to achieve the asymmetric cell fates.
Stem cells have the unique ability to undergo asymmetric division which produces two daughter cells that are genetically identical, but commit to different cell fates. The loss of this balanced asymmetric outcome can lead to many diseases, including cancer and tissue dystrophy. Understanding this tightly regulated process is crucial in developing methods to treat these abnormalities. Here, we report that during a Drosophila female germline stem cell asymmetric division, the two daughter cells differentially inherit histones at key genes related to either maintaining the stem cell state or promoting differentiation, but not at constitutively active or silenced genes. We combine histone labeling with DNA Oligopaints to distinguish old versus new histones and visualize their inheritance patterns at a single-gene resolution in asymmetrically dividing cells in vivo. This strategy can be applied to other biological systems involving cell fate change during development or tissue homeostasis in multicellular organisms.
Kinetoplastid-based infections are neglected diseases that represent a significant human health issue. Chemotherapeutic options are limited due to toxicity, parasite susceptibility, and poor patient compliance. In response, we studied a molecular target-directed approach involving intervention of hexokinase activity – a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of T. brucei hexokinase 1 (TbHK1, IC50 = 9.1 μM), low mammalian cytotoxicity (IMR-90, EC50 > 25 μM), and no appreciable activity on whole BSF parasites was optimized to afford probe 4f with improved TbHK1 potency and, significantly, efficacy against whole BSF parasites (TbHK1, IC50 = 0.28 μM, BSF LD50 = 1.9 μM). Compound 4f and analogs also inhibited the hexokinase enzyme from Leishmania major (LmHK1), albeit with less potency compared to TbHK1, suggesting that inhibition of the glycolytic pathway may be a promising opportunity to target multiple, disease-causing trypanosomatid protozoa.
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