FIGURE 2.

Decreased DOT1L activity is associated with increased developmental potential. The Waddington landscape envisions the process of cellular specification as a ball rolling down an incline, losing developmental potential as a new identity is gained. Cells cannot easily change lineage after cell fate decisions are specified, which become entrenched by epigenetic modifications. Totipotent cells in the 2-cell (2C) embryo, are on top of the landscape as they can differentiate into any cell type of the body or extra-embryonic tissue, whereas the inner cell mass of the pluripotent blastocyst differentiates into the embryo. DOT1L activity maintains chromocenter heterochromatin to oppose transition of pluripotent embryonic stem cells (ESCs) to a 2C-like cell state in vitro (Yang et al., 2022). DOT1L is not required for self-renewal of ESCs (Jones et al., 2008; Cao et al., 2020). DOT1L disruption inhibits differentiation in vivo and in vitro (Jones et al., 2008; Barry et al., 2009; Feng et al., 2010; Liao and Szabó, 2020). Conversely, inhibiting DOT1L greatly enhances reprogramming from unipotent somatic cells indicating H3K79me is a barrier for pluripotency acquisition (Onder et al., 2012; Wille and Sridharan, 2022). Thus, DOT1L activity is a determinate of developmental potential. The phenotype upon DOT1L disruption is depicted by: +, = , −. Created with BioRender.com.