5.12: Histone Modification

The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.

Acetylation

The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase, removes the acetyl group from acetylated histones. The lysine amino acids at position 4 and 9 of N-terminal histone tail are often acetylated and deacetylated. Acetylation increases the negative charge of histones. This weakens the DNA-histone interaction resulting in loosening of chromatin and increased access to DNA. For example, in the erythroid cells, beta-globin gene is associated with acetylated histones that increase its expression. In non-erythroid cells where the gene is inactive, it is found to be associated with nonacetylated histones.

Methylation

The histone tails at the lysine 9 position of histone H3 can be di- or tri-methylated by enzyme histone methyltransferase. This methylation can initiate the binding of nonhistone proteins and increase chromatin compaction. Methylation increases the positive charge on the histones, resulting in increased affinity between negatively charged DNA and histones and higher chromatin compaction. Repressed chromatin, also known as heterochromatin, is highly methylated.

Summary table of histone modifications and their effect on gene expression

The histone codes or modifications are epigenetically inherited, meaning these modifications are not genetically coded. Hence, these modifications are faithfully passed on to the next cell during each cell division as an epigenetic memory.

A nucleosome contains a protein core that is made up of four histone core proteins: H2A, H2B, H3, and H4.

In addition to these four standard core histones, eukaryotes also possess a few variants of each histone, with the exception of H4. 

The amino-terminal tails of the core standard and variant core histones protrude from the nucleosomes and are highly unstructured and mobile.

These tails, comprising of about 30 amino acids, are subjected to several forms of covalent modifications such as the acetylation of lysines, phosphorylation of serines, and mono-, di-, or tri-methylation of lysines. 

The reactions that lead to these modifications are catalyzed by different enzymes such as methyltransferases, acetylases, kinases. These groups of enzymes are collectively referred to as the ‘writers.’ 

The reactions that catalyze the removal of these chemical groups are catalyzed by enzymes such as demethylases, deacetylases, and phosphatases. These enzymes are collectively referred to as the ‘erasers.’

Amongst the numerous possible combinations of different histone variants and amino-terminal end modifications, only certain coordinated sets are known to occur. Some of these combined sets of modifications encode a specific signal for the cell. 

For example, one set of modifications signals DNA damage and the need for repair. Another signals gene expression, while others signal gene silencing or chromatin modification like the establishment and spread of heterochromatin. 

This encoding system is referred to as the ‘Histone Code.’ 

The signals encoded in these modifications are decoded by specific regulatory proteins called ‘readers.’ These proteins and multiprotein complexes contain various small domains, each of which recognizes a particular histone mark. 

They bind tightly to a region of chromatin that contains several different histone marks and attract additional protein complexes with catalytic activities. This leads to specific biological functions such as chromatin modifications, gene expression, and gene silencing.