||Wednesday, 11 October 2023, 17:30～19:00
||7th Floor, Seminar Room 1,IDAC Center for Basic Aging Research
||Small Molecule Components of GATA Factor-dependent Regulatory Networks Governing the Development and Function of Stem and Progenitor Cells
||Emery H. Bresnick, Ph.D
||University of Wisconsin School of Medicine and Public Health
||Hozumi Motohashi (Dept. Gene Expression Regulation・ext8550)
||A plethora of malignant and non-malignant hematology disorders involve disruption of gene- and protein-regulatory networks. This is exemplified by genetic and epigenetic alterations in mechanisms involving members of the GATA transcription factor family, which cause anemia, immunodeficiency, bone marrow failure and leukemia (Katsumura et al. Blood 2017; Churpek and Bresnick, JCI 2019). Our studies to elucidate GATA1- and GATA2-dependent networks revealed numerous small molecule transporters and biosynthetic enzymes as network components (Fujiwara et al. Mol. Cell 2009; Johnson et al. Science Adv. 2015; Mehta et al. Cell Rep. 2017; Zwifelhofer et al. PLOS Genet. 2020; Johnson et al. JEM 2020). By establishing and maintaining small molecule ensembles in cells, these components generate cell-autonomous and non-cell-autonomous mechanisms that govern the development and function of hematopoietic stem/progenitor cells and their progeny. I will discuss recent multiomic analyses that led to the discovery that GATA1 dictates the levels of bioactive lipids by regulating genes encoding the enzymatic machinery. Utilizing genetic editing to rewire the regulatory circuitry and complementary pharmacological approaches, we established a mechanism in which GATA1-regulated bioactive lipids control cytokine receptor signaling as an essential determinant of erythrocyte development. We expect that this mechanistic framework can be extrapolated to GATA factor mechanisms operating at various levels of the hematopoietic system physiologically and in inflammation-related pathological states.