Chromatin is not an inert structure, but an instructive DNA scaffold that regulates DNA's multiple uses in response to external cues. A major component of chromatin that plays a key role in this regulation is the modification of histones. The list of these modifications is growing, and the intricacies of their operation are just beginning to be understood. It is clear that histone modifications play an important role in most biological processes involving DNA manipulation and expression.
Histone modifications work through two main mechanisms. The first involves modifications that directly affect the overall structure of chromatin, both short and long distances. The second involves modifications that modulate (positive or negative) effector molecule binding. Our review has a transcriptional focus, simply reflecting the fact that most studies involving histone modifications also have this focus. However, histone modifications are equally implicated in the regulation of other DNA processes such as repair, replication and recombination.
1. Direct structural disturbance. Histone acetylation and phosphorylation effectively reduce the positive charge of histones, which has the potential to disrupt electrostatic interactions between histones and DNA. This can result in a less compact chromatin structure, which facilitates the entry of protein machinery, such as those involved in transcription, into DNA.
2. Regulate the binding of chromatin factors. A number of chromatin-associated factors have been shown to interact specifically with modified histone through many different domains. This suggests the existence of multivalent proteins and complexes with specific domains that can recognize multiple modifications and other nucleosomal features simultaneously.
Histone modifications do more than just provide a dynamic binding platform for various factors. They can also disrupt interactions between histones and chromatin factors. For example, H3K4me3 prevents the NuRD complex from binding to the N-terminal tail of H3. The simple mechanism that seems plausible since NuRD is a general transcriptional repressor and H3K4me3 is a marker of active transcription. H3K4 methylation also disrupts the binding of the PHD finger of DNMT3L to the H3 tail. In fact, this N-terminal region of H3 appears to be important for regulating these types of interactions, although regulation is not limited to modification by K4. For example, phosphorylation of H3T3 prevents the INHAT transcriptional repressor complex from binding to the H3 tail.