New screening approach identifies proteins that control human gene expression

Researchers at University of California San Diego have developed a large-scale screening approach that identifies proteins controlling a fundamental step in gene expression known as alternative polyadenylation (APA). APA determines where an RNA molecule is cut and finished before it is translated into protein, influencing the stability, localization and function of thousands of genes. Although APA occurs in more than 70% of human genes, and abnormalities in APA have been implicated in cancer, neurological disorders and other diseases, many of the proteins that regulate the process have remained unknown. Understanding this hidden machinery could offer new possibilities for treating diseases related to APA dysregulation.

To address this gap, the research team screened 879 human RNA-binding proteins using a custom reporter system designed to measure how individual proteins influence APA. The screen identified 63 high-confidence activators of poly(A) site usage, the most important step of the APA process. Excluding known positive controls, only seven of these proteins had previously been associated with APA, indicating that the vast majority represent newly identified regulators. Follow-up experiments confirmed that many of these proteins alter RNA processing in cells and affect distinct groups of genes involved in specific biological functions.

The researchers also trained a protein language model to predict APA regulators directly from protein sequences. The model successfully identified activators in an independent validation set and highlighted regions of proteins that appear critical for their function. This approach could help accelerate the discovery of RNA regulatory proteins and provide insight into how they work.

Among the most unexpected findings were new roles for two proteins called GRB2 and RNPS1, neither of which was known to be associated with APA previously. The study showed that both proteins can directly interact with components of the cellular machinery responsible for APA. Beyond identifying new regulators, the researchers developed a programmable RNA-targeting platform that can recruit proteins to specific poly(A) sites, creating a potential framework for scientists to manipulate RNA processing in a targeted manner.

The study ("Large-scale tethered screen of RNA-binding proteins reveals novel regulators of poly(A) site selection") published on June 26, 2026, in Molecular Cell and was led by Gene Yeo, professor of cellular and molecular medicine at UC San Diego School of Medicine, director of the Center for RNA therapeutics and technologies and director of the Sanford Stem Cell Innovation Center at the Sanford Stem Cell Institute, in collaboration with Youngsheng Shi, professor of microbiology and molecular genetics at UC Irvine.