부산대학교 도서관

Histone H3 lysine79 (H3K79) methylation was found to be enriched on transcriptionally active genes and catalyzed by DOT1L, a solely known H3K79 methyltransferase. Mouse Dot1L has been shown to play a pivotal role in cell cycle progression, transcriptional regulation, DNA damage response, and leukemogenesis. Genetic studies have demonstrated that conventional knockout (KO) mutation of Dot1L resulted in embryonic lethality with cardiovascular defects in mouse. In the present study, therefore, we investigated in vivo cell-autonomous function of Dot1L in endothelial cells by using conditional KO strategy.We demonstrate that Tg(Tek-cre)-mediated endothelial Dot1L KO (Dot1LECKO) causes lethality at various developmental stages with lymphatic anomalies including hypoplastic and blood-filled lymph vessels, chylous ascite and edema on back skin, yet exhibits normal blood vessel endothelial cell (BEC) development. A completely penetrated lymphatic agenesis was found in mesenteric lymph vessel. Multiple Cre strains and in vitro ES cell differentiation model were used to explore how epigenetic memory (H3K79me) in BEC controls lymphatic endothelial cell (LEC) development. Our preliminary data suggests that Dot1L depletion causes defect of LEC differentiation via downregulation of genes important for lymph vessel formation. We propose that H3K79 methylation by Dot1L in BEC ensures precise LEC differentiation and lymph vessel network formation. Currently, we are studying underlying mechanism of regulatory role of Dot1L in LEC development in molecular and genome-scale levels.