Examples of Crosstalk Between Post-Translational Modifications

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Pathway Description:

Post-translational modifications (PTMs) have recently emerged as major regulators of protein function. Originally described in histones, these various chemical modifications (methylation, acetylation, phosphorylation, sumoylation, and more) have now been identified in non-histone proteins as well. Early work defined a putative role for each of these modifications, for instance, acetylation correlates with activation and methylation with repression. However, more recent studies indicate that some of these modifications could trigger either activation or silencing in a context dependent manner. For instance, methylation of histone H3K9 lysine correlates with repression, while methylation of H3K4 lysine correlates with activation. Furthermore, each of these moieties can be either mono-, di- or tri-methylated, and depending on the degree of methylation, the biological output will be completely different. Until recently, PTMs were considered independently, under the assumption that their functions would not be related to one another. It is now clear that PTMs work in concert, and the "cross-talk" between different modifications determines the final biological read-out. In this context, some modifications can influence others, and it appears that specific combinations of these modifications can form a dynamic "code". We provide a few examples of this type of cross-talk above. Although each of the modifications shown here are occurring in cis, there are now clear examples, at least for histones, where modifications in one histone molecule can regulate modifications in other histones in trans.

Although there are now many examples of these “functional networks”, it is likely that we have just begun to scratch the surface. Better antibodies and novel technologies will help to complete this cross-talk puzzle, for which the specific fine-tuning appears critical to determine life as we know it.

Selected Reviews:

• Latham JA, Dent SY (2007) Cross-regulation of histone modifications. Nat. Struct. Mol. Biol. 14(11), 1017–1024.
• Yang XJ, Seto E (2008) Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell 31(4), 449–61.
• Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4), 693–705.
• Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447(7143), 407–12.