Loss of ERG function causes lymphatic vessel malformations and primary lymphoedema

Transcription factor networks are crucial for the regulation of endothelial cell gene expression during vascular development and homeostasis. A recent analysis of 269 rare diseases in 77,539 individuals revealed an association between loss-of-function variants in ERG, encoding an ETS transcription factor, with primary lymphoedema. However, the pathogenicity of such variants and possible mechanisms of ERG-associated lymphatic vessel dysfunction remains to be established. Here, we have further identified and characterised lymphoedema-associated ERG genetic variants, revealing pathogenic mechanisms ranging from differential ERG subcellular localisation to altered DNA-binding and impaired transactivation. We confirm a role for ERG in regulating lymphangiogenesis using in vitro assays and a lymphatic endothelium-specific Erg deletion mouse model. Furthermore, we characterise the transcriptional and epigenomic landscape of human dermal lymphatic endothelial cells, identifying a unique role for ERG in regulating lymphatic gene programs, including the establishment of cooperative TF networks with PROX1 and GATA2. Our studies identify ERG as a master regulator of lymphatic endothelial cell transcriptional networks and uncover the mechanisms that underpin a novel causative gene for primary lymphoedema.