Overview
We combine chemical biology with genetic perturbations at scale to illuminate molecular mechanisms that control gene regulation.
CRISPR Mutational Scanning
We are interested in studying protein function and small molecule mechanism of action, particularly in the context of gene regulation. To do this, we are developing CRISPR mutational scanning approaches to systematically mutagenize target proteins directly in cells. We are expanding these approaches to investigate protein complexes and pathways at scale, where our long-term aim is to uncover novel therapeutic opportunities.
Publications and Preprints:
- Base editor scanning reveals activating mutations of DNMT3A. Garcia et al. ACS Chemical Biology (2023).
- Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma. Kwok et al. Nat. Chem. Biol. (2023).
- Activity-based CRISPR scanning uncovers allostery in DNA methylation maintenance machinery. Ngan et al. eLife (2023).
- Base editor scanning charts the DNMT3A activity landscape. Lue et al. Nat. Chem. Biol. (2023).
- Profiling the landscape of drug resistance mutations in neosubstrates to molecular glue degraders. Gosavi et al. ACS Cent. Sci. (2022).
- CRISPR-suppressor scanning reveals a nonenzymatic role of LSD1 in AML. Vinyard et al. Nat. Chem. Biol. (2019).
Chemical Approaches for Functional Genomics
We are developing molecular biology tools leveraged with next-generation sequencing to study chromatin conformation, transcription, and translation. To enable these and other efforts, we are interested in the chemical synthesis of small molecules and their functional derivatives. These probe molecules will be derived both rationally and also from natural products.
Publications and Preprints:
- DNA methylation insulates exons from CTCF loops near nuclear speckles. Roseman*, Siegenfeld* et al. bioRxiv (2023).
- Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery. Siegenfeld*, Roseman* et al. Nat. Commun. (2022).
- Discovery of C13-aminobenzoyl cycloheximide derivatives that potently inhibit translation elongation. Koga et al. J. Am. Chem. Soc. (2021).
- A versatile synthetic route to cycloheximide and analogues that potently inhibit translation elongation. Park et al. Angew. Chem. Int. Ed. (2019).