Limited predictive performance on novel synthetic sequences. (A) Schematic of mouse Hprt1 locus and synthetic payload profiling strategy (Camellato et al. 2024). mESC DNase-seq is shown at top. mESCs were engineered to replace their Hprt1 locus with Big-IN LP, which was used to deliver three synthetic payloads: human HPRT1 locus, SynHPRT1R (reversed but not complemented human HPRT1 locus), and SynHPRT1R^noCpG (SynHPRT1R with all CpG removed) payloads. Engineered cells were characterized by ATAC-seq. (B) Schematic of human HPRT1 locus. Shown is DNase-seq of human H7_hESC and corresponding Enformer prediction. (C) ATAC-seq and Enformer accessibility predictions for engineered mESCs. Shown synthetic payloads (HPRT1, SynHPRT1R, and SynHPRT1R^noCpG) profiled and predicted accessibility. Schematics of each synthetic payload are shown above the accessibility tracks. Reversed payloads (SynHPRT1R and SynHPRT1R^noCpG) are flipped horizontally, and SynHPRT1R^noCpG was centered to match HPRT1 coordinates. Enformer false-positive predictions are highlighted in gray.