Connecting the DOTs on Cell Identity

Abstract

DOT1-Like (DOT1L) is the sole methyltransferase of histone H3K79, a modification enriched mainly on the bodies of actively transcribing genes. DOT1L has been extensively studied in leukemia were some of the most frequent onco-fusion proteins contain portions of DOT1L associated factors that mislocalize H3K79 methylation and drive oncogenesis. However, the role of DOT1L in non-transformed, developmental contexts is less clear. Here we assess the known functional roles of DOT1L both in vitro cell culture and in vivo models of mammalian development. DOT1L is evicted during the 2-cell stage when cells are totipotent and massive epigenetic and transcriptional alterations occur. Embryonic stem cell lines that are derived from the blastocyst tolerate the loss of DOT1L, while the reduction of DOT1L protein levels or its catalytic activity greatly enhances somatic cell reprogramming to induced pluripotent stem cells. DOT1L knockout mice are embryonically lethal when organogenesis commences. We catalog the rapidly increasing studies of total and lineage specific knockout model systems that show that DOT1L is broadly required for differentiation. Reduced DOT1L activity is concomitant with increased developmental potential. Contrary to what would be expected of a modification that is associated with active transcription, loss of DOT1L activity results in more upregulated than downregulated genes. DOT1L also participates in various epigenetic networks that are both cell type and developmental stage specific. Taken together, the functions of DOT1L during development are pleiotropic and involve gene regulation at the locus specific and global levels.