The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications (known as ''histone marks'') to histone proteins, primarily on their unstructured ends. Together with similar modifications such as

DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...

it is part of the

epigenetic code The epigenetic code is hypothesised to be a defining code in every eukaryotic cell consisting of the specific epigenetic modification in each cell. It consists of histone modifications defined by the histone code and additional epigenetic modificati ...

. Histones associate with DNA to form

nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...

s, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

(taken to be the tail) that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

The hypothesis

The hypothesis is that chromatin-DNA interactions are guided by combinations of histone modifications. While it is accepted that modifications (such as

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...

ADP-ribosylation ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. ...

, ubiquitination,

citrullination Citrullination or deimination is the conversion of the amino acid arginine in a protein into the amino acid citrulline. Citrulline is not one of the 20 standard amino acids encoded by DNA in the genetic code. Instead, it is the result of a post-tr ...

SUMO is a form of competitive full-contact wrestling where a ''rikishi'' (wrestler) attempts to force his opponent out of a circular ring (''dohyō'') or into touching the ground with any body part other than the soles of his feet (usually by thr ...

-ylation and

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

) to histone tails alter chromatin structure, a complete understanding of the precise mechanisms by which these alterations to histone tails influence DNA-histone interactions remains elusive. However, some specific examples have been worked out in detail. For example, phosphorylation of

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

residues 10 and 28 on histone H3 is a marker for chromosomal condensation. Similarly, the combination of phosphorylation of

residue 10 and acetylation of a

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

residue 14 on histone H3 is a tell-tale sign of active transcription. Histone modifications

Modifications

Well characterized modifications to histones include: *

Methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

: Both lysine and arginine residues are known to be methylated. Methylated lysines are the best understood marks of the histone code, as specific methylated lysine match well with gene expression states. Methylation of lysines H3K4 and H3K36 is correlated with transcriptional activation while demethylation of H3K4 is correlated with silencing of the genomic region. Methylation of lysines H3K9 and H3K27 is correlated with transcriptional repression. Particularly, H3K9me3 is highly correlated with constitutive heterochromatin. Methylation of histone lysine also has a role in DNA repair. For instance,

H3K36me3 H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri- methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies. There are diverse modi ...

is required for homologous recombinational repair of DNA double-strand breaks, and H4K20me2 facilitates repair of such breaks by non-homologous end joining. *

Acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...

—by HAT (histone acetyl transferase); deacetylation—by HDAC (histone deacetylase): Acetylation tends to define the 'openness' of chromatin as acetylated histones cannot pack as well together as deacetylated histones. *

Phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

* Ubiquitination * SUMOylation However, there are many more histone modifications, and sensitive

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is use ...

approaches have recently greatly expanded the catalog. A very basic summary of the histone code for gene expression status is given below (histone nomenclature is described here):

Histone H2B

* H2BK5ac

Histone H3

* H3K4me1 - primed enhancers * H3K4me3 is enriched in transcriptionally active promoters. * H3K9me2 -repression * H3K9me3 is found in constitutively repressed genes. * H3K27me3 is found in facultatively repressed genes. * H3K36me * H3K36me2 *

is found in actively transcribed gene bodies. *

H3K79me2 H3K79me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 79th lysine residue of the histone H3 protein. H3K79me2 is detected in the transcribed regions of active genes. ...

* H3K9ac is found in actively transcribed promoters. * H3K14ac is found in actively transcribed promoters. * H3K23ac * H3K27ac distinguishes active enhancers from poised enhancers. *

H3K36ac H3K36ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 36th lysine residue of the histone H3 protein. H3K36ac has not been widely studied but it is very widely conserved a ...

* H3K56ac is a proxy for de novo histone assembly. * H3K122ac is enriched in poised promoters and also found in a different type of putative enhancer that lacks H3K27ac.

Histone H4

H4K5ac H4K5ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H4 protein. H4K5 is the closest lysine residue to the N-terminal tail of histone H4. ...

H4K8ac H4K8ac, representing an epigenetic modification to the DNA packaging protein histone H4, is a mark indicating the acetylation at the 8th lysine residue of the histone H4 protein. It has been implicated in the prevalence of malaria. Nomenclature ...

H4K12ac H4K12ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 12th lysine residue of the histone H4 protein. H4K12ac is involved in learning and memory. It is possible that restor ...

H4K16ac H4K16ac is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the acetylation at the 16th lysine residue of the histone H4 protein. H4K16ac is unusual in that it has both transcriptional activation ...

H4K20me H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for geno ...

H4K91ac H4K91ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 91st lysine residue of the histone H4 protein. No known diseases are attributed to this mark but it might be implica ...

Complexity

Unlike this simplified model, any real histone code has the potential to be massively complex; each of the four standard histones can be simultaneously modified at multiple different sites with multiple different modifications. To give an idea of this complexity, histone H3 contains nineteen lysines known to be methylated—each can be un-, mono-, di- or tri-methylated. If modifications are independent, this allows a potential 4¹⁹ or 280 billion different lysine methylation patterns, far more than the maximum number of histones in a human genome (6.4 Gb / ~150 bp = ~44 million histones if they are very tightly packed). And this does not include lysine acetylation (known for H3 at nine residues), arginine methylation (known for H3 at three residues) or threonine/serine/tyrosine phosphorylation (known for H3 at eight residues), not to mention modifications of other histones. Every

in a cell can therefore have a different set of modifications, raising the question of whether common patterns of histone modifications exist. A study of about 40 histone modifications across human gene promoters found over 4000 different combinations used, over 3000 occurring at only a single promoter. However, patterns were discovered including a set of 17 histone modifications that are present together at over 3000 genes. Therefore, patterns of histone modifications do occur but they are very intricate, and we currently have detailed biochemical understanding of the importance of a relatively small number of modifications. Structural determinants of histone recognition by readers, writers and erasers of the histone code are revealed by a growing body of experimental data.

References

External links

Cellsignal.com Histone Modifications with function and attached references

Histone Code Overview sheet

Histone Modification Guide
{{DEFAULTSORT:Histone Code Epigenetics de:Histonmodifikation#Histon Code