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 klf2a during valve morphogenesis. We report two novel transcription factors with a function in heart valve formation in zebrafish: egr1 and klf2b. Genome-wide analysis of gene expression reveals that the endocardial transcriptional programs modulated by klf2a, klf2b, and egr1 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, in vivo phenotypic analyses show that VEGF receptor 1 (flt1) is a target of egr1 and klf2b during early valvulogenesis. These findings suggest that klf2a, klf2b, and egr1 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.

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