Transcriptional Activity and Histone Methylation

M ethylation of Lys and Arg residues of histones has been identified as another tool for modification of histone structure and for regulation of transcriptional activity. The methylation of lysine residues of histones is an example of an epigenetic code that is used to establish transcriptionally inactive states both in heterochromatin and in euchromatin.The best characterized example is histone H3, which is found to be methylated at K4, K9 and K20. These methylations have a differential effect on transcriptional activity. 

Methylation at K9 is associated with transcriptional inactivation and establishment of a heterochromatin state. K9 methylation by the methyltransferase SUV39 directs binding of the transcriptional repressor HP1, which is a component of transcriptionally inactive heterochromatin (Fig. 1.36). SUV39, HP1 and histone deacetylase enzymes have been found to be associated with inactive, hypophosphorylated complexes between the tumor suppressor pRb and the transcription factor E2F (see Chapter 13). 

These observations indicate that the SVU39/HP1 complex is involved in transcriptional silencing at heterochromatic loci and can be specifically recruited to genes by association with transcriptional regulators. 

In contrast, methylation at K4 of H3 is correlated with transcriptionally active states of chromatin. The K4 methylation appears to be absent from histones with methylation at K9, but colocalizes with acetylation at K9, indicating a positive cooperation of acetylation and methylation of distinct Lys residues during the establishment of a transcriptionally active state. For yeast histones, a link between methylation and acetylation at Lys residues and phosphorylation at Ser residues of histone H3 has been discovered (Nakayamaet al. 2001), defining a conserved pathway of sequential histone modifications during heterochromatin assembly. These modifications are recognized by specific proteins that are part of multiprotein assemblies in heterochromatin. 

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