We often talk of DNA, but know little about histone modification.

Chromosomes are made up of complexes of histone proteins wrapped around by DNA.  Histones and the coiled DNA form a basic unit known as the nucleosome.

A nucleosome consists of eight histones, each a chain of amino acid groups. The chemical modifications that occur on the side chains of these amino acids are histone modifications, which typically include methylation, phosphorylation, and acetylation.

Mingxuan Wu’s lab recently published a paper on histone modification onAngewandte Chemie, a journal of the German Chemical Society.

Theoretically, all cells in a living being share the same genes. Cells with different functions are formed through histone modification regulation. If we imagine the genetic information carried by DNA as a vast map, histone modification would be the checkpoints that work together with the map.

As histone modification errors can cause diseases, Wu’s lab has explored using chemistry to regulate histone modifications over the past three years.

Wu targeted one transpeptidase, a specific enzyme isolated from Staphylococcus aureus. Previous studies had characterized this transpeptidase as only playing a connecting role. Wu’s team proposed and verified that transpeptidase could serve as a replacement to catalyze the metathesis reaction.

The substrate of transpeptidase can be either a long peptide carrying a transmembrane signal or a complete full-length protein, which could potentially replace chemically synthesized polypeptide modifications on intracellular histones and achieve modification and editing. However, original transpeptidases cannot do this in the nucleus due to their dependence on calcium ions. Wu’s team modified the transpeptidase through gene editing and obtained a new variant, 6M-Srt, that doesn’t depend on calcium ions.

With this breakthrough, the next challenge was how to bring specific chemically modified sequences into the nucleus. Wu’s team used penetrating peptides, also known as Trojan peptides, to carry cargo across cellular membranes.

Led by the new transpeptidase variant 6M-Srt, the chemically modified substrate polypeptide and histone H3L underwent a metathesis reaction, and engraved the modifications onto the histone.

Wu’s work has proved the feasibility of this method, but histone reprogramming in natural cells is not so efficient. His next challenge is to further transform the transpeptidase. In his laboratory, Wu’s team faces the complexity of life up front as a single change in one amino acid or chemical molecule can lead to completely different results. Chemistry serves as a fulcrum to explore the secrets of life.