A new player enters the field – Succinylation a novel transcriptional activator

The packaging of DNA influences directly or indirectly all cellular processes such as transcription. Post-translational histone modifications (PTMs) influence how DNA is packaged. However, our understanding of how these PTMs regulate transcription is still limited. The lab of Prof. Robert Schneider, of the Institute for Functional Epigenetics at Helmholtz Zentrum München does pioneering work in the field of new PTMs on histone proteins. Just recently, the team around Dr. Lara Shahidian published their findings showing how histone succinylation enhances transcription.

@Model of how succinylation affects transcription; epigenetics@HMGU

The human body is composed of more than 200 different cell types. Each of our body’s cells contains the same hereditary information encoded in around 30,000 individual genes. Each gene serves as a plan for a protein that can be produced during a process called gene expression. However, cells do not express all genes, only the ones required for their function, e.g. being a heart cells. Thus, different cell types express different sets of genes. But, how do cells control which genes are active?

The genes are encoded in the DNA, which is safely stored inside the nucleus of each cell. To fit the 2 m DNA into the small nucleus, it is packed into a structure called chromatin. The degree of packaging at a gene determines if the gene is expressed or not. Open chromatin structures allow genes to be active, whereas genes packaged into very dense chromatin structures are not expressed. By remodeling chromatin structure, epigenetic mechanisms control the ON-and-OFF status of genes and ensure that the right genes are expressed in each cell type.  

Chromatin consists of a repeating array of nucleosomes looking like beads on a string. These nucleosomes are formed by eight histone proteins around which the DNA is wrapped. Histones are small positively charged proteins and the negatively charged DNA binds to it. Epigenetic mechanisms involve changes in nucleosomes making the DNA more or less tightly bound to the histone proteins, such as the addition of distinct PTMs to the histones. For example, acetylation – one of the best studied histone PTM - reduces the positive charge of histones, destabilizes nucleosomes and opens up the chromatin structure. Thus, histone acetylation is often found on genes that need to be available for gene expression.

Even though, histone PTMs and their regulatory roles have been extensively studied over the past 60 years, there is still a lot to learn and additional, novel types of histone PTMs have recently entered the field. The laboratory of Prof. Schneider is world-leading in the field of histone modification research, shedding light on how novel types of PTMs can regulate transcriptional activity.

Now the research team around Dr. Lara Shahidian and Prof. Schneider published their findings about the “young” histone PTM, succinylation** in EMBO Reports. “Succinylation has the potential to alter the charge of histones. Thus, we were curious to know whether this mark is implicated in transcription”, said Dr. Shahidian. Since it is a novel mark in the field, the group of researchers had to raise antibodies against the mark at first. “The antibodies allowed us to characterize the exact genomic location of the mark,” explained Prof. Schneider. “We could identify that it is enriched at regions where transcription starts.”

Interestingly, the group of researchers could observe that succinylation can stimulate transcription by destabilizing nucleosomes and thus increasing accessibility to the DNA. “For the first time, we could gain insights into the role of a site-specific histone succinylation in transcription”, added Dr. Shahidian. “We also identified enzymes that can add the succinylation mark. These enzymes require specific metabolites for its activity. Thus, our next steps are to study the links between cellular metabolism and chromatin via histone succinylation and their implication in metabolic diseases such as diabetes.”

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Further information:

* The process of transcription, whereby our genetic information stored in DNA is transferred to transportable RNA molecules so that proteins (translation: RNA – Proteins) can be made, is the initial step of gene expression.

 ** Histone succinylation belongs to the group of histone acylations, together with acetylation, butyrylation, crotonylation, and malonylation. All histone acylations have the potential to change the charge of the histone. Interestingly succinylation converts the positive into a negative charge. PTMs occur on specific amino acids of the histone proteins, e.g. acetylation and succinylation are found on lysines (K). The histone PTM studied by Shahidian et al. is H3K122succ meaning that the lysine at the position 122 of the histone H3 is succinylated.