A dual role of H4K16 acetylation in the establishment of yeast silent chromatin

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
The EMBO Journal (Impact Factor: 10.43). 06/2011; 30(13):2610-21. DOI: 10.1038/emboj.2011.170
Source: PubMed


Discrete regions of the eukaryotic genome assume heritable chromatin structure that is refractory to transcription. In budding yeast, silent chromatin is characterized by the binding of the Silent Information Regulatory (Sir) proteins to unmodified nucleosomes. Using an in vitro reconstitution assay, which allows us to load Sir proteins onto arrays of regularly spaced nucleosomes, we have examined the impact of specific histone modifications on Sir protein binding and linker DNA accessibility. Two typical marks for active chromatin, H3K79(me) and H4K16(ac) decrease the affinity of Sir3 for chromatin, yet only H4K16(ac) affects chromatin structure, as measured by nuclease accessibility. Surprisingly, we found that the Sir2-4 subcomplex, unlike Sir3, has higher affinity for chromatin carrying H4K16(ac). NAD-dependent deacetylation of H4K16(ac) promotes binding of the SIR holocomplex but not of the Sir2-4 heterodimer. This function of H4K16(ac) cannot be substituted by H3K56(ac). We conclude that acetylated H4K16 has a dual role in silencing: it recruits Sir2-4 and repels Sir3. Moreover, the deacetylation of H4K16(ac) by Sir2 actively promotes the high-affinity binding of the SIR holocomplex.

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    • "Although Sir2 itself has previously been implicated in H3K56 deacetylation, it is possible that alone it is not able to compensate for the loss of Hst3 and Hst4. In addition, its role in H3K56 deacetylation is controversial and there are several reports presenting conflicting data (Oppikofer et al. 2011; Xu et al. 2007; Yang et al. 2008). It has recently been shown that HDACs mediate the stability of heterochromatin through the suppression of histone turnover (Aygun et al. 2013) and given that H3K56ac is conducive to DNA unwrapping at the entry/exit site of the nucleosome, removal of this modification may facilitate this process by inducing a more closed conformation at these sites. "
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    • "This revealed that acetylation of K16 decreases the affinity of Sir3 for chromatin and affects chromatin structure. In contrast, the Sir2-4 subcomplex exhibited increased affinity when K16 was acetylated, suggesting a dual role of K16 acetylation, i.e. the recruitment of Sir2-4 and the repelling Sir3 (Oppikofer et al., 2011). "
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    • "This preference could simply reflect a higher affinity of ISWI for nucleosomes carrying H4K16ac. Alternatively, H4 tail availability and access of ISWI to the nucleosome substrate might be facilitated by H4K16ac-promoted unfolding of the fibre [30]–[32], [39], [46]. Other scenarios are also possible. "
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