New Method Improves Mapping of RNA-Protein Interactions

Bioengineers at the University of California San Diego have developed a technology that comprehensively maps RNA-protein interactions inside human cells. These interactions regulate critical cellular functions, such as gene expression and stress responses, but until now only small subsets were accessible to study.

PRIM-seq, the new method described recently in Nature Biotechnology, captures the exact moments when RNAs and proteins physically interact by tagging proteins and chemically linking them to their target RNAs. These linked pairs convert into unique DNA barcodes, which can be read by common sequencing technologies, producing a detailed catalog of RNA-protein contacts in a single experiment. Applied to two human cell lines, the approach revealed over 350,000 interactions, including many previously unknown, alongside established RNA-binding proteins as well as unexpected ones.

One notable finding was phosphoglycerate dehydrogenase (PHGDH), a gene previously linked to Alzheimer’s disease. The study found PHGDH binds messenger RNAs involved in cell survival and nerve growth, suggesting additional roles in brain health. Another discovery involved a long noncoding RNA, LINC00339, which interacts with several membrane proteins and is elevated in some cancers, hinting at mechanisms driving tumor progression.

Co-first author Shuanghong Xue explained how these RNA-protein contacts could serve as targets for drug development: “Interactions that act as control knobs for disease become drug targets—either the RNA, the protein partner, or the contact surface between them.” Blocking harmful interactions or strengthening protective ones offers new therapeutic strategies. The technology also locates the precise protein regions and RNA sequences involved, aiding the design of targeted treatments.

Much work remains, however. “For most of the new interactions we’ve uncovered, their exact biological roles still need to be worked out,” added senior author Sheng Zhong. “The main advance here is that we’ve created a comprehensive, unbiased map of potential RNA-protein partnerships. This opens the door for future research to figure out which ones drive disease, which ones are protective, and how we can target them with drugs.”