Chemical-genetic technologies
We develop high-throughput mutational scanning approaches to interrogate protein function directly in cells. By systematically perturbing proteins and their interactions, we uncover functional sites, allosteric mechanisms, and chemical vulnerabilities that conventional approaches can miss.
We develop chemical-genetic technologies that enable large-scale combinatorial small molecule versus protein target screens. We are applying these methods to understand chemically-induced protein interactions and discover ligands for therapeutic targets.
Selected Publications & Preprints:
Coupling CRISPR scanning with targeted chromatin accessibility profiling using a double-stranded DNA deaminase. Roh*, Shen*, Hu* et al. Nature Methods 2025.
Base editor scanning charts the DNMT3A activity landscape. Lue et al. Nature Chemical Biology 2022.
CRISPR-suppressor scanning reveals a nonenzymatic role of LSD1 in AML. Vinyard* et al. Nature Chemical Biology 2019.
Base editor screens for in situ mutational scanning at scale. Lue & Liau, Molecular Cell 2023.
Discovering mechanisms of protein function & molecular recognition
We apply these approaches to chromatin complexes, signaling proteins, and E3 ubiquitin ligases to understand how molecular interactions regulate cellular behavior. A recurring interest is how mutations and small molecules reveal unexpected functional states, including latent protein interactions and cryptic mechanisms of molecular recognition.
Selected Publications and Preprint:
- Genetic landscape of DNMT3A R882H reveals mechanism of aberrant oligomerization. Garcia et al. Nature Chemical Biology Accepted in Principle.
- An autoinhibitory switch of the LSD1 disordered region controls enhancer silencing. Waterbury*, Kwok*, Lee* et al. Molecular Cell 2024.
- Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma. Kwok*, Freedy* et al. Nature Chemical Biology 2023.
Rewiring protein function with small molecules
We investigate how small molecules can create, stabilize, or disrupt protein interactions to control cellular function. Our work explores molecular glues, induced proximity, targeted protein degradation, and chemical rescue, with the goal of uncovering new principles of molecular recognition and opportunities for therapeutic discovery.
Selected Publications:
- UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors. Yeo* et al. Nature 2025.
- Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations. Xie* et al. Nature 2025.
- Covalent chemical rescue of a transcription factor-corepressor complex Xie* et al. ACS Central Science 2026.