Mesoscale proximity labeling at chromatin to study small molecule mechanism of action [RNAseq_4h_782]

Proximity labeling traditionally identifies interactomes of a single protein or RNA, though this approach limits mechanistic understanding of biomolecules functioning within complex systems. Here, we demonstrate a strategy for deciphering ligand-induced changes to global biomolecular interactions by enabling proximity labelling at the mesoscale, across an entire cellular system. By inserting nanoscale proximity labelling catalysts throughout chromatin, this system, MesoMap, provided new insights into how HDAC inhibitors regulate gene expression. Furthermore, it revealed that the orphaned drug candidate, SR-1815, regulates disease-linked Syngap1 gene expression through direct inhibition of kinases implicated in both neurological disorders and cancer. Through precise mapping of global chromatin mobility, MesoMap promotes insights into how drug-like chemical probes induce transcriptional dynamics within healthy and disease-associated cellular states. Overall design: Mouse primary cortical neurons from Syngap1 conditional rescue (Syngap1+/ls) mice were treated with either DMSO (vehicle) or SR-1815 for 4h and total RNA was collected for sequencing. N=5 for SR-1815 and DMSO.