BPS2026 – Whole-genome 3D architectural screen reveals modulators of brain DNA structure in vivo

Chromatin folding across genomic length scales encodes cell identity and context-dependent function, yet systematic perturbation of 3D genome organization remains challenging. Conventional chromatin conformation capture assays, while powerful, typically require substantial input per condition (often on the order of 1–10M cells) and are run across separate batches, which can complicate side-by-side evaluation of many perturbations, and in heterogeneous cell states. We introduce Plate-C, a plate-based chromosome conformation capture workflow that enables high-throughput, parallel measurement of chromatin architecture across thousands of matched conditions within a single experiment. Using Plate-C, epigenetic perturbations in cerebellar granule cells and HEK cells revealed dramatic, pathway-linked reorganization of chromatin features. Building on this foundation, we apply Plate-C to human iPSC-derived neurons and their pluripotent precursors to define neuronal architectural features and assess sensitivity to perturbations. In parallel, we develop a Plate-C-adapted computational framework enabling robust estimation and comparison of compartment scores and other mesoscale features across treatments. Together, these advances establish Plate-C as a scalable platform for causal interrogation of 3D genome regulation during neurodifferentiation and in drug screens, providing a comparative map of how molecular pathways modulate chromatin architecture in human neurons.