Essential regulation of heparan sulfate proteoglycan signalling controls cell behaviour to support cardiac development

Abstract

Heparan sulfate proteoglycan (HSPG)-dependent signalling is essential for cardiac development, yet how HSPGs are regulated in the forming heart is unknown. Here, we show that the extracellular heparan sulfate modifier, SULF1, expressed by the epicardium, dynamically regulates HSPG sulfation to fine-tune the magnitude and duration of signalling to impact cell fate and cardiac morphogenesis. Single cell genomics and lineage tracing studies reveal Sulf1 to be strongly co-expressed with Wt1 in the epicardium, with reduction of both coinciding with epithelial-mesenchymal transition and quiescence. CUT&RUN-seq revealed transcriptional control of Sulf1 by WT1 which directly impacts essential HSPG-dependent downstream signalling. Our study highlights, for the first time, essential fine-tuning of HSPG-dependent signalling to modulate key processes for heart formation.