Shuo Gu, Ph.D.

Functional Genomics of miRNA Biogenesis in Cancer

Our research focuses on understanding how genetic alterations in the miRNA biogenesis machinery drive human disease, particularly cancer. While miRNAs are broadly implicated in tumorigenesis, identifying the specific miRNA changes that functionally contribute to disease has remained a major challenge.

We take a genetics-first approach by studying recurrent cancer-associated mutations in core miRNA processing factors. These mutations provide a unique entry point to uncover causal relationships between disrupted miRNA biogenesis and disease phenotypes. Importantly, systematic characterization of these mutations not only has the potential to reveal new therapeutic opportunities, but also serves as a powerful strategy to uncover fundamental principles governing miRNA biogenesis and regulation.

A major focus of our work is on mutations in DICER1, a central enzyme in miRNA processing. Using isogenic cell systems, animal models, and biochemical reconstitution, we demonstrated that cancer-associated RNase IIIb hotspot mutations do not simply cause loss of function. Instead, they induce a rewiring of miRNA output, characterized by depletion of 5p miRNAs and a surprising gain of function of specific 3p miRNAs. Mechanistically, we showed that this effect arises from altered strand selection by Argonaute, revealing a previously unappreciated layer of regulation in miRNA biology.

Building on these findings, our current efforts aim to systematically define the functional landscape of disease-associated variants in miRNA biogenesis genes. We are developing high-throughput platforms, including prime editing–based saturation mutagenesis, to map how individual mutations impact miRNA processing, strand selection, and downstream gene regulation. These studies will enable mechanistic classification of variants, improve interpretation of patient mutations, and uncover new regulatory logic within the miRNA pathway.

Mechanisms of miRNA Processing and Regulation

Our earlier work established key principles governing miRNA maturation and diversification. We uncovered how structural features of primary miRNAs influence processing accuracy and demonstrated that miRNA isoforms (isomiRs) are regulated and functionally distinct. We also defined how 3′ tailing and trimming pathways modulate miRNA stability and targeting.

These mechanistic insights now serve as a foundation for interpreting how disease-associated mutations perturb the miRNA pathway. By integrating structural, biochemical, and genomic approaches, we aim to connect molecular defects in RNA processing with their phenotypic consequences.

Toward Therapeutic Targeting of miRNA Pathways

A long-term goal of our research is to translate mechanistic understanding of miRNA dysregulation into therapeutic strategies. By identifying the specific miRNAs and regulatory pathways altered by pathogenic mutations, we seek to uncover actionable vulnerabilities in cancer and other diseases.

Our work suggests that mutant miRNA processing factors can create selective dependencies on specific miRNAs. Targeting these aberrant miRNA networks may provide new opportunities for precision medicine, particularly in cancers associated with defined genetic lesions such as DICER1 syndrome.

Shuo Gu received his B.A. in Tsinghua University, China. He completed his Ph.D. training in the laboratory of Dr. John Rossi at Beckman Research Institute, City of Hope, Los Angeles. Shuo Gu undertook his postdoctoral training in the laboratory of Dr. Mark Kay at Stanford University Medical School, Palo Alto. Both his Ph.D. and postdoctoral research focused on the mechanisms of RNA interference and microRNA pathways, and their applications in gene therapy. He joined the RNA Biology Laboratory (formerly the Gene Regulation and Chromosome Biology Laboratory) in 2013 as a Stadtman Investigator.