CaMKKβ regulates transcription factor Elf2 gene methylation to maintain endothelial junctional barrier integrity

The Ets transcription factors induce the expression of Tie2 and VE-cadherin. However, the regulation of these factors remains unknown. Here, we found that the gene encoding the Ets factor Elf2 was hypermethylated in Camkkβ-deficient (<i>Camkkβ</i> ^-/-) mice. Notably, these mice exhibited suppressed expression of Elf2, Tie2, and VE-cadherin. Additionally, either the depletion of CaMKKβ in human lung endothelial cells (EC) or EC-specific deletion of <i>Camkkβ</i> in mice led to a decrease in the expression of Elf2, Tie2, and VE-cadherin. <i>In vivo</i> inhibition of DNA methyltransferases or EC-specific expression of wild-type CaMKKβ restored the expression of Elf2, Tie2, and VE-cadherin in <i>Camkkβ</i> ^-/- mice. We find that methyl CpG binding protein MeCP2 repressed Elf2 expression. In EC-restricted <i>Elf2</i> knockout mice, the lung endothelial barrier was compromised due to the suppressed expression of Tie2 and VE-cadherin. Together, these findings underscore the crucial role of CaMKKβ in regulating endothelial junctional barrier integrity by controlling Elf2 expression.