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.

Antagonistic H3K79me-H3K9ac crosstalk determines elongation at housekeeping genes to promote pluripotency

“…Catalytic inhibition or depletion of DOT1L greatly increases cellular reprogramming efficiency from somatic to iPSCs 24,25 . Taken together, these findings indicate that low levels of DOT1L are conducive to, and even enhance pluripotency, but it is necessary for establishing somatic identity 26 .…”

DOT1L interaction partner AF10 controls patterning of H3K79 methylation and RNA polymerase II to maintain cell identity

“…Inhibition or loss of DOT1L greatly enhances the reprogramming of induced pluripotent stem cells from somatic cells (Jackson et al, 2016; Onder et al, 2012; Wille and Sridharan, 2022a) and promotes formation of totipotent-like cells (Xu et al, 2022; Yang et al, 2022). Thus DOT1L activity is coincident with, and even promotes, a loss of potency (Wille and Sridharan, 2022b).…”

Identification of DOT1L Inhibitor in a Screen for Factors that Promote Dopaminergic Neuron Survival

“…As noted in previous primary publications and in a comprehensive review, DOT1-Like (DOT1L) is the sole methyltransferase of histone H3K79 (Wong et al, 2015, Ferrari et al, 2020, Gray de Cristoforis et al, 2020, Wille and Sridharan, 2022). DOT1L can orchestrate mono- di- or tri-methylation that is correlated with actively transcribing genes (mono- and di-methylation) or repression (tri-methylation).…”

“…The discovery of the linkage between DOT1L and DA neurons in our compound screen here suggests that H3K79me might also play a key regulatory role during DA development. As noted in previous primary publications and in a comprehensive review, DOT1-Like (DOT1L) is the sole methyltransferase of histone H3K79 (Wong et al, 2015, Gray de Cristoforis et al, 2020, Wille and Sridharan, 2022. DOT1L can orchestrate mono-di-or trimethylation that is correlated with actively transcribing genes (mono-and di-methylation) or repression (tri-methylation).…”