Chromatin-contact atlas reveals disorder-mediated protein interactions

RNA-binding proteins (RBPs) play diverse roles in regulating co-transcriptional RNA-processing and chromatin functions, but our knowledge of the repertoire of chromatin-associated RBPs (caRBPs) and their interactions with chromatin remains limited. Here, we developed SPACE (Silica Particle Assisted Chromatin Enrichment) to isolate global and regional chromatin components with high specificity and sensitivity, and SPACEmap to identify the chromatin-contact regions in proteins. Applied to mouse embryonic stem cells, SPACE identified 1,825 chromatin-associated proteins, >40% of which are annotated as RBPs, indicating their dual roles in chromatin and RNA-binding. SPACEmap showed that about half of chromatin contacts of proteins are mediated by intrinsically disordered regions (IDRs). Additionally, SPACEmap strictly verified chromatin-binding of 422 RBPs by locating their chromatin-contact regions. As an example, we show Dazl co-localization with PRC2 on transcription start sites revealing an independent function from Dazl 3-UTR-binding. Together, our approach provides an unprecedented structural insight into IDR-mediated interactions in native chromatin.