Beyond B-DNA for histone studies
I enjoyed reading the C&EN cover story “Expanding the Histone Code” (June 6, 2022, page 22). I fully agree with the overall characterization of the importance of locating new chemical modifications on histones that package our genes. Methylation and acetylation are the two most frequent modifications; they regulate gene expression by alternating between transcriptional activation and repression. Andrew J. Andrews is correct in saying that “we have to change our thinking from simple on-off switches and inhibitors like we’ve done for years to more complicated systems.” Additionally, we need to do the same with James Watson and Francis Crick’s canonical right-handed double-stranded (ds) B-DNA structure and histone interactions and expand our view on DNA structure to include non-B-DNA conformations, such as the alternative left-handed DNA (ds-Z-DNA), tightly bent DNA, and looped DNA.
Additionally, other unusual nucleic acids, such as multistranded DNAs (e.g., triplex DNA, G-quadruplex DNA, and i-motif DNA molecules), need to be considered when discussing chemical modifications of histones. These noncanonical DNA structures play important roles in regulating transcriptional gene expression but are usually left out of the molecular biological conversation.
Researchers need to place an emphasis on the relationship between chemical modifications of histones and not just canonical B-DNA but also alternative and multistranded DNA structures. Adding these noncanonical DNA-based structural factors will further expand our knowledge on how the histone code works, adding another layer to its complexity beyond just chemical modifications of proteins, canonical B-DNA, and epigenetics. And investigating the relationships between noncanonical B-DNA structures and histone modifications on gene expression will expand our knowledge of epigenetics.
DNA can no longer be viewed as a static, one-dimensional molecule—namely, B-DNA—but rather as an extremely flexible and dynamic polymorphic polymer that can adopt many different structures on the basis of its sequence and length. This concept must be included in any conversations about expanding (and even cracking) the histone code.
Claude E. Gagna
Bronxville, New York