Complementary functions of the mechanosensitive factors egr1 , klf2b and klf2a instruct the endocardial program

Mechanical forces are key modulators of valvulogenic developmental programs. However, the mechanosensitive gene network underlying this process remains unclear. It is well established that contractile and flow forces activate endocardial expression of the transcription factor during valve morphogenesis. We report two novel transcription factors with a function in heart valve formation in zebrafish: and . Genome-wide analysis of gene expression reveals that the endocardial transcriptional programs modulated by , , and mainly contain non-redundant targets. Several of these targets have been implicated in endothelial-to-mesenchymal transition (EMT). Many of the deregulated genes exhibit changes in chromatin accessibility pointing to potential direct effects of these factors. Finally, phenotypic analyses show that VEGF receptor 1 ( is a target of and during early valvulogenesis. These findings suggest that , , and cooperate for the activation of EMT program in response to mechanosensitive inputs. We propose that the combinatorial action of these factors mediates flow mechanotransduction to control the endocardial program, especially for valve development.