Trends in Genetics
Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation
Section snippets
H3 phosphorylation during mitosis and meiosis
Ser 10 phosphorylation of histone H3 gained considerable interest when this modification was discovered to be associated with chromosome condensation and segregation during mitosis and meiosis [12]. Since this discovery, it has been found that mitosis-specific phosphorylation of histone H3 also occurs at Ser 28 [13] and at threonine 11 (Thr 11) [14]. It is unclear whether these modifications are causally linked. Histone H3 phosphorylation at Ser 10 begins during prophase, with peak levels
Histone H3 phosphorylation during transcription: a modification for rapid induction?
In 1991, Mahadevan and coworkers described the nucleosomal response [a rapid phosphorylation of histone H3 molecules concomitant with activation of the c-fos and c-jun immediate-early (IE) response genes] by stimulating fibroblast cells with growth factors, phorbol esters, inhibitors of protein synthesis and inhibitors of protein phosphatases (Figure 2). The observed timecourse of histone H3 phosphorylation mirrored the known expression profile of these genes, leading the authors to postulate a
Interplay between phosphorylation and other histone H3 modifications
The Ser 10 residue in the N-terminal tail of histone H3 is located in a region of the protein that is also subject to other covalent modifications (Figure 1). For example, Lys 9 and 14 can be acetylated as a prelude to transcriptional activation, whereas methylation of Lys 9 can lead to silencing and formation of heterochromatin. Therefore, these modifications might affect the ability of Ser 10 to be phosphorylated and vice versa, and evidence from in vitro and in vivo experiments supports this
Acetylation versus phosphorylation: synergistic or parallel pathways?
Simultaneous studies on mouse fibroblast cells demonstrated that EGF stimulation leads to the phosphorylation and acetylation of the same histone H3 tail as a result of the nucleosomal response [35]. However, these modifications are each deposited via independent pathways, suggesting that, at least in some cases, histone H3 phosphorylation at Ser 10 is not just a signal for subsequent acetylation at Lys 14. Analysis of c-jun induction suggests that the presence of a phosphorylated histone H3
Histone H3 phosphorylation during transcriptional activation in Drosophila
Evidence from the analysis of gene expression in Drosophila has provided additional examples of genes that appear to follow the independent parallel pathway of histone modification during induction of transcription. Taking advantage of the heat-shock response of Drosophila (a well-defined means of global inactivation of transcription and induction of the heat-shock genes in response to thermal stress 43, 44) the genome-wide distribution of histone H3 Lys 14-acetylation and Ser 10-histone H3
Control of histone H3 phosphorylation by phosphatases
The sequence of events leading to histone H3 phosphorylation during induction of transcription could also possess another layer of complexity, where different kinases are recruited to specific promoters. Because specific transcription factors are known to bind to particular promoters, it could be inferred that these transcription factors might recruit or interact with unique kinases that serve to phosphorylate histone H3 at the nucleosomes of the promoter in question. In this article, we have
Conclusions
Despite numerous studies examining the possible correlation between the phosphorylation of histone H3 and a transcriptionally active state, it is still not clear whether this modification has a direct functional role in transcription or whether it is only a prerequisite for further modification via acetylation of Lys 14.
Current evidence suggests that, at least in some cases, Ser 10 phosphorylation is necessary and sufficient for transcriptional activation without acetylation of additional
Acknowledgements
Work conducted in the authors' laboratory was supported by a U.S.A. Public Health Service Award (GM35463) from the National Institutes of Health.
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