Mechanism of the Long Range Anti-silencing Function of Targeted Histone Acetyltransferases in Yeast

Qun Yu,Joseph Sandmeier,Hengping Xu,Yanfei Zou,Xin Bi

doi:10.1074/jbc.m510140200

Abstract

Transcriptionally silent chromatin in Saccharomyces cerevisiae is associated with histone hypoacetylation and is formed through the action of the Sir histone deacetylase complex. A histone acetyltransferase (HAT) targeted near silent chromatin can overcome silencing at a distance by increasing histone acetylation in a sizable region. However, how a tethered HAT acetylates distant nucleosomes has not been resolved. We demonstrate here that targeting the histone H3-specific HAT Gcn5p promotes acetylation of not only histone H3 but also histone H4 in a broad region. We also show that long range anti-silencing and histone acetylation by targeted HATs can be blocked by nucleosome-excluding sequences. These results are consistent with the contention that a tethered HAT promotes stepwise propagation of histone acetylation along the chromatin. Because histone hypoacetylation is key to the formation and maintenance of transcriptionally silent chromatin, it is believed that acetylation promoted by a targeted HAT disrupts silent chromatin thereby overcoming silencing. However, we show that the acetylated and transcriptionally active region created by a tethered HAT retains structural hallmarks of Sir-dependent silent chromatin and remains associated with Sir proteins indicating that tethered HATs overcome silencing without completely dismantling silent chromatin.

Highlights

Acetylation of the N-terminal lysine residues of histones neutralizes the positive charge they carry, which is believed to alter the property of nucleosomes resulting in a reduction in the degree of chromatin compaction [8]
The spreading model proposes that local acetylation of histones carried out by a targeted histone acetyltransferase (HAT) serves to recruit additional HATs thereby initiating the spread of HAT complexes along the chromatin
When the LexA-binding sites were deleted from strain c, LexAEsa1p or LexA-Gcn5p did not have any effect on the silencing of URA3 [27], indicating that LexA-Esa1p or -Gcn5p overcame silencing only when they were tethered near the silent region

Summary

Introduction

Acetylation of the N-terminal lysine residues of histones neutralizes the positive charge they carry, which is believed to alter the property of nucleosomes resulting in a reduction in the degree of chromatin compaction [8]. The long distance anti-silencing function of tethered LexA-Gcn5p or LexA-Esa1p coincided with the creation of a sizable (Ͼ2 kb) chromatin domain with elevated acetylation of histone H3 or H4 that spanned the target site [27].

Results

Conclusion