How to build the regulatory genome: a constructionist guide to the cis-regulatory code

The cis-regulatory code is exceedingly complex, involving many proteins acting in concert to interpret individual cis-regulatory DNA sequences, which themselves work together to regulate the expression of genes. The Company of Biologists' 2024 Workshop 'Building to Understand: The Constructionist Approach to Studying Gene Regulation' brought together an international, interdisciplinary team of investigators studying how cis-regulatory elements control gene expression. Here, we summarise some of the Workshop's discussions and review how our understanding of genome regulation has been shaped by constructionist approaches, as well as where these approaches may lead in the future. An eventual goal is to be able to design cis-regulatory DNA to have desired functions; therefore, we provide guidance on their design based on current knowledge, while simultaneously highlighting what remains to be discovered.