Sequence design for three-dimensional genome folding using Akita Semifreddo

DNA sequence directs genome folding, which in turn shapes enhancer-promoter communication and gene expression. How to design DNA sequences that produce desired folding patterns remains largely unexplored. Here we present Akita Semifreddo, which combines an efficient "half-frozen" version of the AkitaV2 genome folding model with the Ledidi sequence optimizer to design DNA sequences with desired folding in silico. We demonstrate that this framework enables design for major folding features – boundaries, dots, and flames – with desired positions and strengths. In short, Akita Semifreddo provides a platform for dissecting the sequence grammar of genome folding and engineering synthetic regulatory landscapes.