Proximity labeling tools for studying chromatin interactomes

Studying protein and nucleic acid interactions within chromatin remains challenging, as these events occur in a densely packed and dynamic nuclear environment. Proximity labeling technologies now offer powerful solutions by enabling spatially and temporally resolved characterization of chromatin microenvironments in living cells. Recent advances in labeling chemistry, photocatalytic platforms, and targeting strategies have improved precision and efficiency, broadening their utility across chromatin biology. Here, we review protein-centered proximity labeling approaches-including nanoscale and mesoscale photocatalytic systems, genetically encoded modalities, and antibody-directed labeling-that reveal histone-associated interaction networks and PTM-dependent microenvironments. We also highlight nucleic-acid-centered platforms that use CRISPR guidance, hybridization-based targeting, or structure-specific sensors to map protein complexes at defined genomic loci, diverse RNA species, and noncanonical structures such as G-quadruplexes and R-loops. Together, these technologies are reshaping how chromatin interactomes are measured. We conclude by outlining key challenges and future opportunities that will guide next-generation proximity labeling tools for chromatin research.