Primitive Erythropoiesis in the Mouse is Independent of DOT1L Methyltransferase Activity.

DOT1-like (DOT1L) histone methyltransferase is essential for mammalian erythropoiesis. Loss of DOT1L in knockout (KO) mouse embryos resulted in lethal anemia at midgestational age. The only recognized molecular function of DOT1L is its methylation of histone H3 lysine 79 (H3K79). We generated a methyltransferase mutant () mouse model to determine the role of DOT1L methyltransferase activity in early embryonic hematopoiesis. embryos failed to survive beyond embryonic day 13.5 (E13.5), similarly to KO mice. However, when examined at E10.5, embryos did not exhibit overt anemia like the . Vascularity and the presence of red blood cells in the yolk sacs as well as in the AGM region of embryos appeared to be similar to that of wildtype. In cultures of yolk sac cells, primitive erythroblasts formed colonies comparable to those of the wildtype. Although cultures of definitive erythroblasts formed relatively smaller colonies, inhibition of DOT1L methyltransferase activity by administration of EPZ-5676 minimally affected the erythropoiesis. Our results indicate that early embryonic erythropoiesis in mammals requires a DOT1L function that is independent of its intrinsic methyltransferase activity.