Succinylation of H3K122 destabilizes nucleosomes and enhances transcription

Abstract

Histone post‐translational modifications (PTMs) are key players in chromatin regulation. The identification of novel histone acylations raises important questions regarding their role in transcription. In this study, we characterize the role of an acylation on the lateral surface of the histone octamer, H3K122 succinylation (H3K122succ), in chromatin function and transcription. Using chromatin succinylated at H3K122 in in vitro transcription assays, we show that the presence of H3K122succ is sufficient to stimulate transcription. In line with this, we found in our ChIP assays H3K122succ enriched on promoters of active genes and H3K122succ enrichment scaling with gene expression levels. Furthermore, we show that the co‐activators p300/CBP can succinylate H3K122 and identify sirtuin 5 (SIRT5) as a new desuccinylase. By applying single molecule FRET assays, we demonstrate a direct effect of H3K122succ on nucleosome stability, indicating an important role for histone succinylation in modulating chromatin dynamics. Together, these data provide the first insights into the mechanisms underlying transcriptional regulation by H3K122succ.

Histone succinylation and its function on the nucleosome

“…Enzymes utilize other cofactors, mainly depending on the size of acyl groups confirming the recent studies that the active sites in p300 and KAT2A are structurally incompatible with long‐chain acyl donors 50,51 . Lara Zorro Shahidian et al also suggested that p300/ CBP can succinylate H3K122 preferentially with acetyl‐CoA 28 …”

“…It also verified a strong correlation between gene expression and protein succinylation near the transcriptional start site by showing a correlation between the succinyl‐lysine ChIP signal and gene expression, which further indicates that promoter succinylation is a mark of gene transcriptional activity 27 . Recently, it was also found that H3K122succ is enriched at transcription start sites and can be a mark of active genes, stimulating transcription in vitro and changing the structure of the stable nucleosome 28 …”

“…27 Recently, it was also found that H3K122succ is enriched at transcription start sites and can be a mark of active genes, stimulating transcription in vitro and changing the structure of the stable nucleosome. 28 These experiments all prove that histone Ksuc is closely related to gene expression in vitro, similar to Kac, by weakening the affinity between DNA and histones to reduce the stability of the nucleosome and chromosomes and to promote the separation of DNA and protein, which can promote the binding of transcription factors to DNA and then contribute to transcription. However, there are still many questions regarding how succinylation regulates the stability, repair and kinetics of the nucleosome and chromosomes; for example, the genes promoted by histone succinylation in vivo still need to be identified using experimental evidence, and whether the Ksuc of histones in vivo is indeed an essential mark of DNA repair needs further elucidation.…”

“…Many studies suggest that enzymes can catalyse histone succinylation. Research shows that p300 succinylates a synthetic peptide in the histone tail sequence in vitro 11,22,28 . Atsushi Yokoyama et al offered sophisticated evidence showing that histone succinylation in the nucleus is an enzymatic process.…”

“…Research shows that p300 succinylates a synthetic peptide in the histone tail sequence in vitro. 11,22,28 Atsushi Yokoyama et al offered sophisticated evidence showing that histone succinylation in the nucleus is an enzymatic process. Although this study extracted histones from HepG2 cell nuclei as the histone succinylation substrates, which did not show Ksuc activity, it was found that enzymemediated histone succinylation indeed occurred in an SP 1.0 M KCl fraction of nuclear extracts.…”