Structural Biochemistry/Fast signals and slow marks: the dynamics of histone modifications

Introduction
During cell differentiation, most multi-cellular organisms form their distinctive gene expression pattern. Over time, this pattern is maintained over the course of many cell divisions even though the initiating signal is gone. Actively transcribed regions are characterized by specific histone modifications. The role of histones is that it is the most important protein component of chromatin. These findings confirm that a histone code uses histone post-translational modifications to translate chromatin structures into the genome with a form of stability.

Chromatin regulates gene expression
DNA (in eukaryotic cells) is wrapped around histone proteins, forming chromatin. Chromatin's basic unit is the nucleosome, which is formed by a histone octamer that consists of two molecules of each of the four core histones: H2A, H4, H3, H2B. The histone octamer also consists of 147 base pairs of DNA wrapped around it on the left-handed helix. Individual nucleosomes pack against each other to form higher order chromatin structures to regulate DNA accessibility. The nucleosome core is created by the globular domains of histones. The nucleosome core doesn't need the N-terminal tails of histone molecules because the histone N-termini don't form crystals in crystallographic studies; but, they are extremely important to chromatin function. It's not completely proven that histone modifications are a cause or a consequence of the activity of a gene. To determine the role of histone modifications, there's results on their targeting to specific genomic loci, their stability and dependence towards one another. The histone code hypothesis was creating because histone-modifying enzymes were discovered as well as the genome-wide mapping of histone modifications.

Genome-wide mapping studies of histone modifications
The genome-wide map purpose is to detect similarities between histone modification patterns and also specific states of gene activity. For example, modifications including H3K4me2,3 and H3K36me2,3 are located in actively transcribed regions and overlap one another. With these overlapping areas with gene activity, this information was used to figure out regions of transcription for untranslated RNA molecules. In a different example, modifications like H3K27me3 and H4K20me3 are frequently mapped to regions where transcription is repressed. This shows that histone modifications can be landmarks for inactivity.

Histone modificationes during transcription
Transcription and DNA assembly are important in finding out when a modification pattern is created and copied. One of the first histone-modifying enzymes characterized at the molecualr level was HAT (acetyltransferase Gen5). HAT was characterized to be a transcriptional co-activator in yeast which linked histone acetylation to gene activation. Genome-wide mapping studies show that acetylated histones can be found at most actively transcribed regions.

Histone modifications during chromatin assembly
Histone modifications are deposited during chromatin assembly and it also observes modifications that occur during activation or represseion of a certain gene. This is extremely important because when newly synthesizes histones are formed and moved into the chromatin, the histone modifications need to maintain the chromatin structure.

Histones are synthesized in the cytoplasm and then it's moved to the nucleus. Most histone synthesis is coupled with S-phase progression to meet the needs of the increased histones. An exception if the histone variant H3.3, which is synthesized into a replication-independent manner. Right after synthesis, histones get a modification pattern and associate with histone chaperones. Histone chaperones help with the deposition of histones onto DNA and they are grouped in the H3/H4 binding factors like Asfl.

Like mentioned above, newly synthesized histones carry a specific histone modification pattern and lysine 5 and lysine 12 of H4 become acetylated and a fraction of H3 is acetylated at lysine 18 and lysine 1. During the transportation from the cytosol, then the nucleus, and then to incorporate new chromatin at the replication fork, histones receive more modifications like monomethylation of lysine 9.

Inheritance of a putative epigenetic code
An epigenetic code is beneficial to initiate the generate and inherit functional chromatin states. In order for this to happen, there are requirements that need to be met:

(i) the system needs to initiate the generation of the code

(ii)the system needs to translate the modifications into varied chromatin states

(iii) the system needs to allow copying of a particular modification pattern from old histones to the ones that are newly synthesized.

Conclusion
There needs to be a mechanism that copies histone modification patterns during cell division if slow turnover of histone methylations want to have the cell pass its epigenetic information to future generations. The turnover is slow because for lysine di- and trimethylations on histones, the reestablishment of methylations on newly sytnhesized histones is slow. This slow turnover allows the cell to have time (if it needs to) to change the modification pattern on a specific gene or copy the previously existing one.

Recent investigations has led many to believe that histone modifications can facilitate the stabilization of gene expression when there's no incoming signal(s). But, there are some modifications, like lysine acetylation, that integrates incoming signals.