Similarly, ChIP-seq—while widely used—remains limited by antibody availability and specificity with peaks that typically span 100 bp or more (Luo et al., 2022). Previous applications in plant systems demonstrated that analysis of small fragments from light chromatin digests could detect thousands of discrete footprints (Savadel et al., 2021), enabling genetic analysis of cistrome dynamics (Engelhorn et al., 2025). This pattern is consistent with a dual role for CTCF as an insulator and a scaffold for enhancer-promoter interactions shown to be required to activate hypoxia-specific gene networks (Kakani et al., 2025; Ren et al., 2017). These findings corroborate those from prior studies reporting the existence of novel vascular endothelial growth factor A (VEGFA)-responsive regulatory elements in endothelial cells (Zhang et al., 2013). Motif analysis further supported this idea, with gain-of-footprint peaks being enriched for FOS, JUN, and CTCF motifs (Figure 6A).