The diverse functions of Dot1 and H3K79 methylation

Abstract

DOT1 (disruptor of telomeric silencing; also called Kmt4) was initially discovered in budding yeast in a genetic screen for genes whose deletion confers defects in telomeric silencing. Since the discovery ∼10 years ago that Dot1 and its mammalian homolog, DOT1L (DOT1-Like), possess histone methyltransferase activity toward histone H3 Lys 79, great progress has been made in characterizing their enzymatic activities and the role of Dot1/DOT1L-mediated H3K79 methylation in transcriptional regulation, cell cycle regulation, and the DNA damage response. In addition, gene disruption in mice has revealed that mouse DOT1L plays an essential role in embryonic development, hematopoiesis, cardiac function, and the development of leukemia. The involvement of DOT1L enzymatic activity in leukemogenesis driven by a subset of MLL (mixed-lineage leukemia) fusion proteins raises the possibility of targeting DOT1L for therapeutic intervention.

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

“…MLL-rearranged mixed lineage leukaemia is driven by chromosomal translocations that result in an oncogenic fusion protein comprising the amino terminal region of MLL and the carboxy terminus of one of B70 translocation partners 14 , and pharmacological targeting of MLL translocation complexes was recently shown to reverse oncogenic activity of MLL fusion proteins in leukemia 15 . A subset of MLL fusion partners, including AF4, AF9 and AF10, aberrantly recruit DOT1L to select genomic loci leading to increased H3K79 methylation and transcriptional activation of genes essential for leukemogenesis 16 . Recently, the antileukemic activity of DOT1L inhibition by either genetic or pharmacological approaches resulted in selective killing of MLL-AF4/9/10 translocation carrying cells 10,17 .…”

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

“…Methylations on different residues and sometimes to different degrees (i.e., tri-, di-or mono-) represent differential transcriptional statuses. Generally, transcription activation is associated with H3K4me3/2 at promoter, and H3K36me3/2 and H3K79me3/2 across the transcribed region, while transcription silencing correlates with H3K27me3/2 at promoter and H3K9 and H4K20 methylation in heterochromatic regions [59][60][61]. However, accumulating evidence has challenged this generalized view, arguing for a more context-dependent role of histone methylation in transcription regulation [62].…”

“…H3K79 methylation H3K79 methylation, catalyzed by Kmt4 (or Dot1L), is associated with active transcription and usually enriched in the gene body [61]. Kmt4-depleted ESCs appear to self-renew with pluripotency markers expressed but have a lower proliferation rate [122].…”

In situ histone landscape of nephrogenesis

“…46 Developmental studies have shown that H3K79me3 is absent in the zygote and even in the blastocyst, suggesting that Dot1l functions post-early embryogenesis stages. 47 Indeed, Dot1l-knockout mice die at E10.5 from cardiovascular defects and severe anemia. 28 The function of Dot1l in the developing kidney is unknown but it has been suggested that Dot1l-H3K79 methylation plays a role in terminal differentiation of the collecting duct.…”