Bulky Histone Modifications May Have an Oversized Role in Nucleosome Dynamics

Inside the nucleus of eukaryotic cells, the genetic information required to run all processes of life is wrapped around histone proteins into nucleosomes. To orchestrate the selection of specific genetic information and to facilitate DNA-dependent transactions occurring in the context of nucleosomes, accessibility of DNA must be spatiotemporally altered. In this issue, Krajewski proposes an intriguing hypothesis for how chemical attachment of large, bulky histone modifications can have oversized influence on chromatin dynamics.^[1]

How is a change in genome accessibility and functionality achieved through chemistry? Specific combinations of histone modifications recruit effector proteins, and small histone modifications (acetylation, methylation) can alter nucleosome charge and/or subtly affect nucleosome dynamics. Here, Krajewski argues that when the chemical modification approaches the size of a histone, such as ubiquitylation and SUMOylation, gross structural distortions and large-scale changes in nucleosome dynamics occur. Thus classical descriptions of the effects of histone modification may underestimate the consequences of these bulky histone marks.

This model provides an intriguing framework for understanding the biological consequences of bulky histone modifications as well as the potential interplay between multiple histone modifications. Regulated installation of large histone modifications is associated with DNA-dependent processes including transcription and replication. Krajewski suggests that this added bulk may trigger spontaneous, transient, and reversible increases in histone dynamics allowing DNA translocating enzymes to traverse nucleosomes more easily. The potential to distort native structure of canonical nucleosomes may expose intermediate nucleosome structures that can be specifically recognized by nucleosome-interacting proteins. Minor nucleosome instabilities resulting from smaller histone modifications may accelerate deposition of bulky histone modifications through allosteric effects. A tunable range of nucleosome dynamics that crescendos with the addition of bulky modifications may be written within the histone code.

A supporting model has been proposed by Morrison et al. relating to H3 tail interactions with histone reader domains.^[2] These researchers found that, although a histone reader may bind strongly to its target peptide in solution, binding in the context of a nucleosome is inhibited because the histone tail interacts with DNA. Histone modifications can alter the histone tail dynamics, decrease interactions with DNA and increase binding of the histone reader to the histone tail. Highlighted here is the importance not only of the presence of a modification for signaling, but also of how a modification can interact with and change the context of that signaling. Krajewski’s hypothesis suggests that this context can be extremely unpredictable, given the range of understudied bulky histone modifications.

While Krajewski presents a strong biophysical argument for the potential bulky groups to distort the nucleosome through steric effects, structural work may present a conflicting story. The structure of the SAGA deubiquitinating module in complex with ubiquitylated H2B shows recognition in the context of a nucleosome, and suggests that ubiquitin incorporation does not impair crystallization of the canonical nucleosome structure.^[3] More recently, the role of ubiquitin in stimulating Dot1L methyltransferase was structurally explained: ubiquitin constrains the sampling space of Dot1L to promote a proper catalysis-competent orientation.^[4] Neither of these structural studies suggests gross nucleosome destabilization. However, increased dynamics may play a physiological role that is not reflected in a structural snapshot.

Krajewski makes a compelling call for scientists in the field to look more closely at how bulky modifications may play a special role in nucleosome dynamics. Future work testing the biological consequences of nucleosome destabilization and clarifying the physiological roles of oversized modifications is essential, but it will be a challenging task. It is likely that the consequences of bulky histone modifications will be multifaceted.