Overview. Our research integrates chemical biology and synthetic biology technologies to develop innovative tools for studying and controlling epigenetic and epitranscriptomic regulation, with a focus on histone and RNA modifications and their roles in transcriptional and post-transcriptional gene expression control. We also apply these strategies and technologies to engineer cell-based therapies for solid tumors and Alzheimer’s diseases Following are some of our research areas:

Develop CIP and sCIP Technologies. CIP technologies are small molecule-based systems that control protein-protein proximity and downstream biological events with high temporal precision. We engineered the plant ABA signaling pathway as a mammalian CIP system using non-toxic, cell-permeable plant hormones, which became one of the most widely adopted CIP systems in the field (Science Signaling 2011). We also developed the auxin-based CIP system using indole-3-acetic acid (IAA), expanding the toolkit for orthogonal control of multiple biological processes simultaneously (Chemical Science 2018). To enable real-time monitoring of dimerization events, we developed the first self-reporting CIP system using a fluorogenic malachite green derivative and fluorogen-activating proteins (Bioconjugate Chemistry 2018). We further developed sCIP technologies that integrate CIP with reactivity-based signal sensing through chemically caged inducers selectively activated by specific cellular signals, including H₂O₂, Fe²⁺, light, and various enzymes (protease, nitroreductase, glycosidase), enabling mammalian cells to translate exogenous or endogenous signals into predefined biological outcomes (ACS Chemical Biology 2015, ACS Synthetic Biology 2017, IJMS 2024, Molecular Therapy 2025). We also developed the first theranostic sCIP system that enables the detection of disease-linked signals and simultaneously producing pre-programmed effects in response (Chemical Science 2023).

Bifunctional Small Molecules and Molecular Glues for RNA regulation. We have developed several classes of bifunctional small molecules and molecular glues that regulate microRNA biogenesis and RNA modifications. We designed and synthesized bifunctional molecules that selectively block Dicer processing of specific pre-microRNAs by bringing a Dicer inactivating agent into proximity with the target pre-miRNA, achieving selective inhibition of miR-21 biogenesis (JACS 2017). We extended this approach to develop light-deactivatable versions of these bifunctional molecules, enabling spatiotemporal control of miRNA biogenesis using photoactivatable chemistry (Bioorganic Chemistry 2018). We further developed bifunctional small molecule-antisense oligonucleotide hybrid approaches for miRNA inhibition (Bioorganic & Medicinal Chemistry 2020) and identified cyclic peptidomimetic scaffolds as a new chemical class for targeting RNA including miR-155 (Molecular Pharmaceutics 2019). These studies established new chemical strategies for selective RNA targeting that complement genetic approaches and can be applied for modulating non-coding RNAs. Extending our bifunctional molecule strategy to RNA modification editing, we recently developed cyclic peptide-based molecular glues that recruit endogenous m⁶A erasers to specific RNA transcripts to achieve site-selective m⁶A editing, demonstrating that CRISPR-free small molecule-based approaches can achieve programmable RNA modification editing (ACS Chemical Biology 2026).

CRISPR-based Epigenome Editing Tools for Chromatin Biology. We have developed several CRISPR-based tools for inducible and reversible editing of histone modifications in living cells. We developed the first chemically controlled dCas9-based system for inducible H3K27 acetylation editing using ABA-CIP, which enabled us to follow the kinetics of histone modification changes and the accompanying gene activity changes to establish causal relationships between epigenetic marks and gene expression (JACS 2017). Using the reversibility of the inducible system, we investigated the stability of ectopically installed histone marks, shedding light on the establishment of epigenetic memory. We also investigated the crosstalk between H3K27 acetylation and H3K4 trimethylation using our CRISPR-based epigenome editing platform, revealing that these two marks have interdependent but non-redundant roles in gene activation (Scientific Reports 2021).

CRISPR-based RNA Modification Editing Tools for Epitranscriptomics Research. We have made significant contributions to the development of CRISPR-based tools for transcript-specific and temporally controlled editing of RNA modifications on endogenous RNAs. We developed the first chemical-inducible dCas13b-based platform enabling site-specific and reversible writing or erasing of m⁶A on chosen RNA transcripts in living cells (Nature Communications 2022). To address the concern of steric disruption from bulky dCas fusion proteins, we developed an inducible split dCas13b system that separates dCas13b into two inactive halves reconstituted only upon ABA addition, achieving “traceless” RNA modification editing with minimal native RNA-protein interaction disruption (JACS 2023). We also developed a complementary platform using the FKBP12 destabilization domain fused to dCas13b for Shield-1-controlled RNA modification editing that limits the expression of the dCas13b complexes to the editing period (Angewandte Chemie 2023).

sCIP-based CAR-T Cell Therapies. We applied our sCIP technologies to develop next-generation CAR-T cell platforms with improved safety and efficacy for solid tumor treatment. We engineered tumor microenvironment (TME)-gated inducible CAR-T cell platforms that use hypoxia-sensing sCIP strategy to selectively activate CAR-T cells only within the immunosuppressive tumor microenvironment, reducing off-tumor toxicities, a major limitation of current CAR-T therapies (Molecular Therapy 2025). We also developed a customizable platform integrating CAR expression with conditional expression of immunotherapeutic payloads in T cells, enabling combinatorial immunotherapy approaches (International Journal of Molecular Sciences 2024).