The Histone H3K79 Methyltransferase Dot1L Is Essential for Mammalian Development and Heterochromatin Structure

Abstract

Dot1 is an evolutionarily conserved histone methyltransferase specific for lysine 79 of histone H3 (H3K79). In Saccharomyces cerevisiae, Dot1-mediated H3K79 methylation is associated with telomere silencing, meiotic checkpoint control, and DNA damage response. The biological function of H3K79 methylation in mammals, however, remains poorly understood. Using gene targeting, we generated mice deficient for Dot1L, the murine Dot1 homologue. Dot1L-deficient embryos show multiple developmental abnormalities, including growth impairment, angiogenesis defects in the yolk sac, and cardiac dilation, and die between 9.5 and 10.5 days post coitum. To gain insights into the cellular function of Dot1L, we derived embryonic stem (ES) cells from Dot1L mutant blastocysts. Dot1L-deficient ES cells show global loss of H3K79 methylation as well as reduced levels of heterochromatic marks (H3K9 di-methylation and H4K20 tri-methylation) at centromeres and telomeres. These changes are accompanied by aneuploidy, telomere elongation, and proliferation defects. Taken together, these results indicate that Dot1L and H3K79 methylation play important roles in heterochromatin formation and in embryonic development.

In situ histone landscape of nephrogenesis

“…27,28 At E15.5, we find that H3K79me3 is more abundant in maturing inner cortical tubules than nascent nephrons or cap mesenchyme (Fig. 7A-C).…”

“…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. 48 Histone methylation occurs on lysine and arginine residues.…”

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

“…Kmt4-depleted ESCs appear to self-renew with pluripotency markers expressed but have a lower proliferation rate [122]. Kmt4 deletion in ESCs also leads to the loss of H3K9me2 and H4K20me3 at centromeres and telomeres, resulting in a less condensed chromatin state [122].…”

“…*Enhanced effi- [197]; defect in neur- [197] ciency by Kmt1c oectoderm contribution inhibitor [73] in teratoma [46] Kmt1d/ NA Reduced NA NA Postimplantation Ehmt1/ efficiency [74] lethality (E8.5-9.5) Glp1 [197] Kmt1e/ NA Reduced Failure and acquiIncorporation to trophe-Peri-implantation Eset/ efficiency [74] sition of trophectctoderm upon blastocyst lethality (E3.5-5.5) the requirement growth rate [122] of Klf4 [74] [122]…”

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…126 However, safety studies are warranted, as genetic disruption in mice results in embryonic lethality. 127 Several downstream targets of the MLL-fusion complex could be possible targets of MLL-rearranged AML. Upregulation of HOX genes is one of the most important hallmarks of MLL-rearranged leukemias.…”