Although histone modifications are associated with gene activities, studies of their causal relationships have been difficult. For this purpose, we developed an inducible system integrating dCas9-based targeting and chemically induced proximity technologies to allow small molecule induced recruitment of P300 acetyltransferase and the acetylation of H3K27 at precise gene loci in cells. Employing the new technique, we elucidated the temporal order of histone acetylation and gene activation, as well as the stability of the installed histone modification.

We report a new strategy to regulate microRNAs (miRNAs) biogenesis by using bifunctional small molecules that consist of a pre-miRNA binding unit connected by a linker to a Dicer inhibiting unit. In this effort, fluorescence polarization-based screening was used to identify neomycin as a pre-miR-21 binding ligand. Although neomycin cannot inhibit miR-21 maturation, linking it to the RNase inhibitor 1 forms the bifunctional conjugate 7A, which inhibits the production of miR-21. We expect that this strategy will be applicable to design other molecules for miRNA regulation.

A new chemical strategy has been developed to generate de novo signaling pathways that link a signaling molecule, H2O2, to different downstream cellular events in mammalian cells. This approach combines the reactivity-based H2O2 sensing with the chemically induced protein proximity technology. By chemically modifying abscisic acid with an H2O2-sensitive boronate ester probe, novel H2O2 signaling pathways can be engineered to induce transcription, protein translocation and membrane ruffle formation upon exogenous or endogenous H2O2 stimulation. This strategy has also been successfully applied to gibberellic acid, which provides the potential to build signaling networks based on orthogonal cell stimuli.

An efficient one-step functionalization of FK506 by the thiol–ene click (TEC) reaction is reported. This approach, which enables rapid and quantitative generation of bioactive FK1012 and FK506 derivatives, should facilitate biomedical applications of FK506-coupled molecules and expand the scope of the TEC reaction in natural product semi-synthesis.