Discover | Design | Engineer 

Proteins interact with RNA to regulate its processing, localization, stability, and translation. Many of these interactions are transient or sensitive to their cellular environment, making them difficult to preserve and investigate.

We develop chemical and molecular engineering approaches to capture these interactions and connect molecular contacts with biological function. A central foundation is Genetically Encoded Chemical Crosslinking for RNA (GECX-RNA). This approach uses genetic code expansion to introduce reactive amino acids at defined positions in proteins. When an interacting RNA is nearby, proximity-enabled chemistry can form a covalent linkage that preserves the molecular contact. Our laboratory builds on this foundation by combining protein engineering, biochemical assays, cellular experiments, and sequencing. These complementary approaches allow us to investigate protein–RNA recognition from individual molecular interfaces to broader patterns of RNA interaction.

Our goal is to create tools that support mechanistic discovery: revealing which interactions occur, how they are organized, and why they matter for RNA regulation.

Questions that motivate us:

• How do proteins recognize RNA in the cellular environment?

• How do individual molecular contacts contribute to RNA binding and regulation?

• How can chemical capture complement existing approaches to studying RNA biology?

Selected Publications:

Sun W, Wang N, Liu H, Yu B, Jin L, Ren X, Shen Y, Wang L. Genetically encoded chemical crosslinking of RNA in vivo. Nature Chemistry 15, 21–32 (2023). PubMed

Liu J, Cai L, Sun W, Cheng R, Wang N, Jin L, Rozovsky S, Seiple IB, Wang L. Photocaged Quinone Methide Crosslinkers for Light-Controlled Chemical Crosslinking of Protein-Protein and Protein-DNA Complexes. Angewandte Chemie International Edition 58, 18839–18843 (2019). PubMed

Biomolecular function depends on how molecules recognize one another, how long they remain associated, and how their interactions respond to the surrounding environment. Engineering these properties offers opportunities to improve therapeutics, diagnostics, and biotechnology.

We develop chemical and molecular engineering tools to create covalent interactions between biomolecules. 

• One direction engineers proteins to covalently engage selected protein targets, with the goal of improving the durability and effectiveness of molecular targeting.

• The other direction creates covalently stabilized protein–RNA complexes, including CRISPR–Cas systems. By strengthening the association between proteins and their RNA partners, we aim to improve complex stability and functional performance for therapeutic, diagnostic, and research applications.

Questions that motivate us:

• How can covalent targeting improve molecular engagement and biological activity?

• How can covalent protein–RNA complexes improve CRISPR–Cas tools for therapeutics and diagnostics?

Selected Publications:

Fianu F, Chen J, Faraji-Gougerdchi B, Duan H, Huang H, Yang R, Sun W, Cheng Y. Coengineering Vapor-Deposited Polycationic Microenvironments and Immobilization Strategy to Enhance β-Galactosidase Kinetics at Acidic pH. ACS Omega 11, 50892–50907 (2026). PubMed

Duan H, Chen J, Fianu F, Sun W, Cheng Y. Nanoscale protonation limits and charge density in polymer films govern the activity of immobilized LacZ under acid stress. Nanoscale 18, 13769–13780 (2026). PubMed

Yu B, Li S, Tabata T, Wang N, Cao L, Kumar GR, Sun W, Liu J, Ott M, Wang L. Accelerating PERx reaction enables covalent nanobodies for potent neutralization of SARS-CoV-2 and variants. Chem 8, 2766–2783 (2022). PubMed

Liu J, Cao L, Klauser PC, Cheng R, Berdan VY, Sun W, Wang N, Ghelichkhani F, Yu B, Rozovsky S, Wang L. A Genetically Encoded Fluorosulfonyloxybenzoyl-L-lysine for Expansive Covalent Bonding of Proteins via SuFEx Chemistry. Journal of the American Chemical Society 143, 10341–10351 (2021). PubMed

RNA processing and stability shape gene expression by influencing which RNA molecules are produced, how long they persist, and how they function. These processes generate biological diversity, yet their complexity makes it challenging to identify the underlying regulatory mechanisms.

We combine sequencing, biochemical approaches, and computational analysis to connect RNA regulation with biological function. 

Our goal is to understand how RNA diversity is generated and regulated, and how these mechanisms shape gene expression and biological function.

Key questions

• How is RNA diversity generated and regulated?

• How do genetic variation and cellular factors influence RNA function?

• How does RNA regulation shape biological outcomes?

Selected Publications:

Sun W, Gao Q, Schaefke B, Hu Y, Chen W. Pervasive allele-specific regulation on RNA decay in hybrid mice. Life Science Alliance 1, e201800052 (2018). PubMed

Gao Q, Sun W, Ballegeer M, Libert C, Chen W. Predominant contribution of cis-regulatory divergence in the evolution of mouse alternative splicing. Molecular Systems Biology 11, 816 (2015). PubMed

Sun W, You X, Gogol-Döring A, He H, Kise Y, Sohn M, Chen T, Klebes A, Schmucker D, Chen W. Ultra-deep profiling of alternatively spliced Drosophila Dscam isoforms by circularization-assisted multi-segment sequencing. The EMBO Journal 32, 2029–2038 (2013). PubMed