The histone demethylase UTX regulates stem cell migration and hematopoiesis
Thieme, S., Gyárfás, T., Richter, C., Özhan, G., Fu, J., Alexopulou, D., Muders, M.H., Michalk, I., Jakob, C., Dahl, A., Klink, B., Bandola, J., Bachmann, M., Schröck, E., Buchholz, F., Stewart, A.F., Weidinger, G., Anastassiadis, K., and Brenner, S.
Regulated migration of hematopoietic stem cells is fundamental for hematopoiesis. The molecular mechanisms underlying stem
cell trafficking are poorly defined. Based on an shRNA library and SDF-1 migration screening assay, we have identified the
histone 3 lysine 27 demethylase UTX (Kdm6a) as a novel regulator for hematopoietic cell migration. Using hematopoietic stem
and progenitor cells from our conditional UTX knockout (KO) mice, we were able to confirm the regulatory function of UTX on
cell migration. Moreover, adult female conditional UTX-KO mice displayed myelodysplasia and splenic erythropoiesis whereas
UTX-KO males showed no phenotype. During development, all UTX-KO female and a portion of UTX-KO male embryos developed a cardiac
defect, cranioschisis and died in utero. Therefore UTY, the male homologue of UTX, can partially compensate for UTX in adults
as well as during development. Additionally, we found that UTX knockdown in zebrafish significantly impairs SDF-1/CXCR4 dependent
migration of primordial germ cells. Our data suggest that UTX is a critical regulator for stem cell migration and hematopoiesis.
