Acetylation of histone H3 at lysine 64 regulates nucleosome dynamics and facilitates transcription

Abstract

Post-translational modifications of proteins have emerged as a major mechanism for regulating gene expression. However, our understanding of how histone modifications directly affect chromatin function remains limited. In this study, we investigate acetylation of histone H3 at lysine 64 (H3K64ac), a previously uncharacterized acetylation on the lateral surface of the histone octamer. We show that H3K64ac regulates nucleosome stability and facilitates nucleosome eviction and hence gene expression in vivo. In line with this, we demonstrate that H3K64ac is enriched in vivo at the transcriptional start sites of active genes and it defines transcriptionally active chromatin. Moreover, we find that the p300 co-activator acetylates H3K64, and consistent with a transcriptional activation function, H3K64ac opposes its repressive counterpart H3K64me3. Our findings reveal an important role for a histone modification within the nucleosome core as a regulator of chromatin function and they demonstrate that lateral surface modifications can define functionally opposing chromatin states.DOI: http://dx.doi.org/10.7554/eLife.01632.001

The chromatin environment shapes DNA replication origin organization and defines origin classes

“…Remarkably, MCM helicase activity is weak on a nucleosome template, and the chromatin remodeling complex FACT is necessary to promote DNA unwinding (Tan et al 2006). In agreement, we found a strong enrichment of H3K64ac strictly centered on the nucleosome at the IS, a new chromatin mark associated with labile nucleosomes in mESCs (Di Cerbo et al 2014). These results suggest a new role for this mark in positioning a labile nucleosome that prevents the accessibility to the IS outside the required time and that can be remodeled when the pre-RC is activated.…”

“…We then investigated whether specific epigenetic marks could explain nucleosome lability. A recent work suggested a role of the previously uncharacterized H3K64ac mark in nucleosome stability and dynamics (Di Cerbo et al 2014). We observed that 86% of origins covered by the H3K64ac ChIP assay were associated with at least one positive probe (Supplemental Fig.…”

H4K44 Acetylation Facilitates Chromatin Accessibility during Meiosis

“…H4K44ac peaks during meiotic DSB formation and repair, which may be favorable for chromatin accessibility of key DSB-associated complexes to initiate and complete meiotic recombination. We propose that H4K44ac may play an important role in increasing chromatin accessibility via nucleosome-DNA destabilization, as has been shown for H3K64ac and H3K122ac on the histone H3 globular domain (Di Cerbo et al, 2014; Tropberger et al, 2013), whereas H4K16ac on the histone H4 tail inhibits inter-fiber interaction (Shogren-Knaak et al, 2006). …”

The use of unnatural amino acids to study and engineer protein function

“…For example, acetylation of lysines within the folded core increase nucleosome dynamics and transcription from reconstituted chromatin templates [21][22][23] and binding of chromatin remodeler RSC (Remodels the Structure of Chromatin) to nucleosomes is enhanced by H3 K14ac [24]. Whereas acetylated H2A, H2B and H3 are efficiently produced by amber suppression, the incorporation of UAAs in histone H4 did not yield amounts sufficient for biochemical experiments probably because of its proteolytic instability.…”