HATs. These enzymes add acetyl groups to lysine residues within the amino termini (also known as the tails) of H3 and H4 histones. This adds a negative charge to the histone tails. The negative charge is believed to cause them to push away from the DNA backbone, resulting in a somewhat less condensed chromatin structure. Hyperacetylation of histones in the promoter regions of genes is associated with active, ongoing gene expression, while histone hypoacetylation is associated with genes that are transcriptionally silent.
The association between histone acetyltransferases and gene activation was first suggested when it was found that the Tetrahymena thermophila HAT p55 was structurally similar to the yeast protein GCN5. GCN5 previously had been shown to be involved in gene activation. Later it was discovered that GCN5-regulated genes are hyperacetylated when active, and that certain mutations in GCN5 that affect its ability to activate target genes result in diminished levels of acetylation of these regions. Histone acetyltransferases also are found in mammalian cells. It is believed that the HATs are recruited to specific genes by specific transcriptional activators.
The activity of the histone acetyltransferases is opposed by histone deacetylases. These enzymes remove acetyl groups from the histone tails, resulting in the repression of gene activation. As with the HATs, these enzymes are believed to be recruited to chromatin by repressor proteins to aid in the inactivation of specific genes.
Transcriptional activation also can be repressed by the methylation of specific cytosine residues found in some genes. It is unclear how methylation results in transcriptional repression, but it is known to cause the inhibition of specific transcriptional activators and to initiate the recruitment of specific repressors that bind methylated DNA. At least one methylated DNA-binding repressor can be isolated from cell extracts together with (and therefore appears to be associated with) histone deactylases, thereby providing a link between methylation and deacetylation and gene inactivation. Other enzymes chemically modify histones by adding or removing phosphate, ubiquitin, and other chemical groups.
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