The language of histone crosstalk

Abstract

It has been suggested that a specific pattern of histone posttranslational modifications and their crosstalk may constitute a code that determines transcriptional outcomes. However, recent studies indicate that histone modifications have context-dependent effects, making their interplay more like a language within the chromatin signaling pathway than a code.

Figure 1. Examples of Histone crosstalk

(A) The first characterized example of histone crosstalk is the stimulation of acetyltransferase activity of GCN5 towards the histone H3 tail by prior phosphorylation (P) of serine 10. Acetylation, Ac. (B) Crosstalk among histone modifications can span more than one histone. Monoubiquitination of histone H2B can lead to the trimethylation of lysine 4 in the histone 3 tail (H3K4) by Set1/COMPASS. However, H3K4 methylation by COMPASS and COMPASS-like complexes can be blocked if the nearby arginine of H3 is already methylated.

Figure 2. Context dependent outcomes of histone crosstalk

(A) Zippo and colleagues (Zippo et al., 2009) uncover a new form of histone crosstalk by studying the transcriptional control of FOS1L, a gene activated in response to serum. Activation requires the binding of PIM1 to the FOS1L enhancer. PIM1 is a kinase responsible for phosphorylation (P) of serine 10 on the histone H3 tail (H3S10). Phosphorylated H3S10 creates a binding site for 14-3-3, a phosphoserine binding protein. Acetylation (Ac) of lysine 16 on the H4 (H4K16) tail occurs through interaction of 14-3-3 with the histone acetyltransferase MOF. Acetylated H4K16 can in turn form a binding site for the bromodomain-containing protein Brd4, a component of P-TEFb, a kinase that phosphorylates the C-terminal domain of RNA Pol II to facilitate transcription elongation. However, at an earlier stage of serum stimulation, an MSK1/2 kinase is recruited to the promoter where it phosphorylates H3S10. 14-3-3 is then recruited to the promoter, but unlike the situation at the enhancer, MOF is not recruited to the promoter. Thus, the timing, location, and perhaps identity of the H3 kinase, and not the H3S10 modification alone, determines downstream events. (B) Another example of how the order of implementation of histone modifications can affect transcription comes from work from Wang et al. (2009). They report that despite correlations between histone acetylation and H3K4 methylation, artificially increasing acetylation through treatment of cells with deacetylase inhibitors (HDACs) does not lead to productive transcription, despite the presence of H3K4 methylation and Pol II recruitment. Therefore, patterns of histone modifications cannot simply be “read”, but have distinct effects depending on the cellular context and upstream signaling events.