How Epigenetics Changes Gene Function(Cont.)

Histone acetylation

Histone modifications by acetylation and deacetylation have been associated with transcriptional activity, regulated by changes in the nucleosome assembly and higher-order chromatin structure (Grant 2001). Histone acetylation involves the attachment of an acetyl group from acetyl-CoA to the α-amino group of the specific lysine (K) side chains (Tollefsbol, 2009) and is carried out by the enzyme histone acetyltransferase (HAT) (Chung 2002).  In some cases acetylation can also occur at serine (S) or arginine (R) residues. The attachment changes the positively charged residue on lysine into a negatively charged residue, which results in the histones having a decreased affinity for DNA. The consequence is that the chromatin structure opens and the DNA is thereby more accessible for transcription (Tollefsbol, 2009). 

Fig. Acetylation of the histone tails is catalyzed by histone acetyltransferase (HAT). Acetylation activates gene expression by making the chromatin structure less dense. Deacetylation is carried out by the enzyme histone deacetylase (HDAC) and results in a denser chromatin structure, and therefore no gene expression. Modified after (Yoshida, 2008).

The reverse, deacetylation, catalyzed by histone deacetylases (HDAC) (Chung, 2002), removes the acetyl groups, which results in increased affinity for the DNA. The chromatin become more condense and is thereby less accessible for transcription, see Figure (Tollefsbol, 2009). The modification can either be global, involving large parts of the chromatin, or promoter specific. The global histone acetylation concerns the general transcriptional activity, while the promoter specific acetylation is important for specific gene activity (Vaissiere, Sawan et al., 2008).

Histone Phosphorylation

Another form of histone modification is phosphorylation, which influences processes such as transcription, DNA repair, apoptosis and chromatin condensation (Grant, 2001). In mitosis the phosphorylation has an essential role, because it correlates with chromosome condensation (Hsu, Sun et al., 2000). The negatively charged phosphate groups are thought to neutralize the charge of the histone tails, resulting in reduced affinity towards the DNA. Studies furthermore indicate that phosphorylation of H3S10 induces HAT activity, leading to an additional increase in transcription activity, caused by acetylation (Grant, 2001).

Histone methylation

Transcriptional activity is also regulated by histone methylation (Grant, 2001), but this form of histone modification is more complex than the others, since it can occur on both lysine and arginine (Allis, 2007). The methylation is catalyzed by the histone methyltransferases (HMTs), which transfer a methyl group from the methyl donor S-adenosyl-L-methionine (SAM) to the residues.  Depending on the residue getting methylated, histone methylation can either enhance or repress transcriptional expression. There are at least 24 identified sites of lysine and arginine methylation on the core histones. These residues have several methylated states, which add another level of complexity (Allis, 2007). Arginine can be either mono- or dimethylated, while lysines can be mono-, di- and trimethylated (Völkela and Angrand, 2006). This gives numerous combination possibilities, which are applicable in tightly regulated processes, such as transcription (Allis, 2007).

There are six well characterized lysine methylation sites: H3K4, H3K9, H3K27, H3K36, H3K79 and H4K20. Methylation on H3K4, H3K27 and H3K79 is associated with activation of transcription, while the others have been linked to repression (Allis et al., 2007).

Histone ubiquitylation

Ubiquitylation (Ub) is different from the other types of histone alterations, mainly because of its size. Ub is a large polypeptide which increases the size, of the histone by approximately two-thirds. Ub can, as histone methylation, be either repressive or activating, depending on which histone it binds to. H2B monoubiquitylation on K123 is activating the DNA transcription and leads to H3K4 methylation, whereas H2A monoubiquitylation on K119 is repressing the transcription (Allis, 2007).