Common and distinct functions of mouse Dot1l in the regulation of endothelial transcriptome

Abstract

Epigenetic mechanisms are mandatory for endothelial called lymphangioblasts during cardiovascular development. Dot1l-mediated gene transcription in mice is essential for the development and function of lymphatic ECs (LECs). The role of Dot1l in the development and function of blood ECs blood endothelial cells is unclear. RNA-seq datasets from Dot1l-depleted or -overexpressing BECs and LECs were used to comprehensively analyze regulatory networks of gene transcription and pathways. Dot1l depletion in BECs changed the expression of genes involved in cell-to-cell adhesion and immunity-related biological processes. Dot1l overexpression modified the expression of genes involved in different types of cell-to-cell adhesion and angiogenesis-related biological processes. Genes involved in specific tissue development-related biological pathways were altered in Dot1l-depleted BECs and LECs. Dot1l overexpression altered ion transportation-related genes in BECs and immune response regulation-related genes in LECs. Importantly, Dot1l overexpression in BECs led to the expression of genes related to the angiogenesis and increased expression of MAPK signaling pathways related was found in both Dot1l-overexpressing BECs and LECs. Therefore, our integrated analyses of transcriptomics in Dot1l-depleted and Dot1l-overexpressed ECs demonstrate the unique transcriptomic program of ECs and the differential functions of Dot1l in the regulation of gene transcription in BECs and LECs.

DOT1-like histone lysine methyltransferase is critical for adult vessel maintenance and functions

“…Consistent with our analysis, silencing DOT1L in HUVECs leads to cell death and reduced capillary sprout formation, which are associated with altered H3K79 methylation and transcription factor ETS-1 binding, resulting in the regulation of VEGFR2 expression [20]. Our previous study revealed that DOT1L regulates distinct sets of transcripts in different types of endothelial cells, likely through H3K79 methylation [24]. One of these gene sets included cellcell adhesion molecules (CLDN1, CLDN11, and PCDHs), which were found to be differentially expressed by DOT1L depletion or overexpression.…”

“…Furthermore, DOT1L promoted BEC migration, A c c e p t e d A r t i c l e tube formation, and sprout formation in vitro and in vivo, primarily by regulating VEGFR2 expression [20]. Remarkably, recent research has demonstrated that DOT1L has a different transcriptional regulatory network depending on the type of endothelial cell, whether LEC or BEC [24]. This indicates the complexity of DOT1L function and highlights its significance in cardiovascular development and lymphangiogenesis.…”