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Disruptions in gene regulatory networks (GRNs), driven by multiple deleterious variants, potentially underlie complex traits and diseases. Hirschsprung disease (HSCR), a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with  RET  and  EDNRB  as its major genes. We previously demonstrated that  RET  transcription in the ENS is controlled by an extensive GRN involving the transcription factors (TFs) RARB, GATA2 and SOX10 and other HSCR genes. We now demonstrate, using human and mouse cellular and animal models, that  EDNRB  is transcriptionally regulated in the ENS by GATA2, SOX10 and NKX2.5 TFs. Significantly,  RET  and  EDNRB  expression is regulated by their shared use of GATA2 and SOX10, and in turn, these TFs are controlled by  EDNRB  and  RET  in a dose-dependent manner. This study expands the ENS development GRN to include both  RET  and  EDNRB , uncovers the mechanistic basis for  RET – EDNRB  epistasis and emphasizes how functionally different genes associated with a complex disorder can be united through a common GRN.

A gene regulatory network explains RET – EDNRB epistasis in Hirschsprung disease