a, Schematic illustrating the types of STARR-seq fragments used in the CAPRA pipeline. Solo fragments (yellow) fully overlap a single cCRE, double fragments (purple) fully overlap a pair of adjacent cCREs, and anchored fragments (green) fully overlap one cCRE and partially overlap an adjacent cCRE. b, Schematic of cCRE-centric mode of CAPRA. Solo and double fragments are counted across input DNA and RNA libraries. Counts are input into DESeq2, which models RNA vs. DNA abundance using a negative binomial framework and estimates log₂ fold changes and significance values. These values quantify enhancer-like (positive, orange) or silencer-like (negative, blue) activity at individual cCREs (solo fragments) or cCRE pairs (double fragments). c, Schematic of paired sweep mode of CAPRA. Solo, double, and anchored fragments are normalized by library size and aggregated into 10 bp bins across the interval between two cCREs. This is done in both directions, sweeping from each cCRE toward the other. Resulting RNA:DNA ratio profiles are compared to underlying sequence features to identify motifs associated with regulatory activity transitions.