Summary of DOT1L in mammalian development. Oocytes express DOT1L (Ooga et al., 2013) and have detectable H3K79me2 (Ooga et al., 2008; Cao et al., 2015). H3K79me2 is quickly depleted after fertilization (Ooga et al., 2008) even though DOT1L is expressed and nuclear. At the 2-cell stage, DOT1L is evicted to the cytoplasm *except when H3K79me2 sharply increased during mitosis (Ooga et al., 2013; Yang et al., 2022). H3K79me2 begins to be detectable at the 4-cell stage when DOT1L mRNA and protein levels are low, and increases concurrent with DOT1L expression until the blastocyst stage (Ooga et al., 2008; Cao et al., 2015). DOT1L-KO is lethal beginning at E11.5 in the mouse (Jones et al., 2008; Feng et al., 2010; Liao and Szabó, 2020). In vitro, ESCs are globally depleted for H3K79me2 compared to somatic cells (Sridharan et al., 2013) and reducing DOT1L activity enhances reprogramming to induced pluripotent stem cells (Onder et al., 2012; Wille and Sridharan, 2022). Wild-type = w.t., and DOT1L knock-out = KO. The relative amount of DOT1L mRNA, protein, and H3K79me2 modification is indicated by: + or not detected = n.d. Created with BioRender.com.