Rewiring nucleosome engagement through chemically induced proximity - chemically induced proximity (CIP) methodology, the use of bivalent molecules to bind and bring together two biomolecules, has…

The National Institute of General Medical Sciences awarded The Leland Stanford Junior University $236,736 on August 9, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop chemically induced proximity methodology for rewiring nucleosome engagement patterns. The project runs through April 30, 2028, with work performed in Palo Alto, California.

The funded research applies bivalent molecules that bind and bring together two biomolecules to promote the interaction of proteins of interest with nucleosomes, the basic chromatin unit. The approach leverages a characterized nucleosome acidic patch ligand to rewire nucleosome engagement, addressing applications in protein degradation, enzymatic promotion, and protein relocalization. The research targets fundamental mechanisms governing transcription through protein-nucleosome interactions, with direct relevance to disease states including cancer, where transcription factor P53 mutations and histone acetyltransferase dysregulation drive oncogenic gene programs through disrupted nucleosomal binding.

Rewiring nucleosome engagement through chemically induced proximity - chemically induced proximity (CIP) methodology, the use of bivalent molecules to bind and bring together two biomolecules, has exploded in popularity over the last decade. CIP molecules serve as both potential therapeutics and useful research tools by chemically promoting important binding events. This has broad applications, such as recruiting E3 ligases to degrade target proteins, sterically block essential protein function, promoting specific enzymatic reactions on target proteins, or relocalizing proteins to other subcellular compartments. However, CIP methodology has yet to be applied to promote the binding of proteins of interest to nucleosomes, the basic unit of chromatin and one of the most abundant substrates in our cells (approaching 1 MM concentrations in nuclei). Nucleosomes are composed of 8 histone proteins (2 each of histones H2A, H2B, H3 and H4), wrapped by ~150 BP of DNA. The histone proteins are often decorated with post-translational modifications on their disordered tails, and contain an acidic patch "landing pad" for hundreds of nuclear proteins in their core domain, all working together to modulate transcription through controlling gene accessibility. Interactions between nuclear proteins and nucleosomes are one of the most important and prolific events in our cells, tightly regulating transcription and frequently disrupted in disease. In one example, the pioneering transcription factor P53 is mutated in more than half of all cancers, with most missense mutations reducing P53 binding to its nucleosomal DNA targets. In another example, the paralogous histone acetyltransferases CBP/P300 are tumorigenic drivers by associated specifically with nucleosome free superenhancer regions to activate specific oncogenic gene programs. We hypothesize that we can rewire nucleosome engagement patterns via CIP methodology, by using a well characterized nucleosome acidic patch ligand, rapta, to chemically promote binding of proteins of interest to chromatin. Specifically, we aim to: (1) rescue nucleosome binding deficient P53-Y220C mutant via chemically induced proximity to chromatin; and (2) inactivate tumorigenic driver CBP/P300 by sequestration into chromatin via chemically induced proximity. These aims propose two complementary but orthogonal strategies for developing novel CIP methodology for therapeutic benefit, by either rescuing chromatin binding function of an important mutant tumor suppressing transcription factor (P53) or sequestering a tumorigenic driver (CBP/P300) into chromatin away from its nucleosome free target sites. More broadly, this proposal aims to develop methodology that chemically promotes one of the most prolific and important binding events in our cells, the interaction between nucleosomes and nuclear proteins. This task is currently impossible without highly engineered cellular systems and one that has to date been neglected by CIP applications. Successful implementation of the proposed work will provide a valuable tool to the epigenetics community and disclose proof-of-concept experiments for novel therapeutic CIP applications; rescuing nucleosome binding function or inactivating target proteins by sequestering them into chromatin, a potentially valuable alternative strategy for when traditional inhibitor and degrader strategies fail.