AsianScientist (Oct. 15, 2019) – A research team in Hong Kong has revealed a fundamental mechanism by which a cell can make changes to its chromatin structure in response to different DNA-associated processes, such as gene expression and DNA damage repair. The findings are published in the journal Molecular Cell.
At the heart of each living cell is chromatin—DNA packaged with proteins called histones. DNA can be tightly or loosely bound to histones; loose packaging indicates an ‘active’ gene region, while tight packaging indicates a ‘silent’ gene region.
Chromatin also contains various ‘road signs’ in the form of chemical modifications to histones, or histone marks, that indicate active, inactive or damaged regions. These histone marks give orders to various chromatin-associated machinery to regulate gene expression, DNA replication and damage repair. Although some well-known chromatin ‘road signs’ such as lysine acetylation and methylation have been well characterized, the biological meanings of many other ‘signs’ remain mysterious.
In this study, scientists led by Associate Professor David Li Xiang at the University of Hong Kong (HKU) went in search of a new chromatin ‘road sign’ and discovered lysine glutarylation at histone H4 (H4K91glu) in human cells. The team showed that the mark is especially abundant in promoter regions of active, ‘open’ chromatin where genes are highly expressed.
“We believe that H4K91glu is a sign for activation of gene expression,” said Li. “This ‘sign’ seems to be conserved in evolution, as we found it in not only human but also mouse, fly, worm and even baker’s yeast cells.”
Besides marking the active genomic region, H4K91glu in fact directly contributes to the formation of the more open accessible chromatin structure facilitating gene expression. The researchers demonstrated that H4K91glu destabilizes the nucleosome, the basic repeating unit of chromatin, and leads to activation or loosening of chromatin.
“It makes perfect sense if you know chemistry, as the mark puts a negative charge on an originally positively charged lysine residue. It therefore causes a charge-charge repulsion within the nucleosome and makes it more prone to falling apart,” Li explained.
Much like an ever-shifting maze, chromatin packaging is highly dynamic, allowing fast switching between gene ‘on’ and ‘off’ states. Meanwhile, when chromatin structure is changed at a specific region, the old histone marks are taken off and the new ones are installed by enzymes.
Li’s team found that an enzyme known as KAT2A, working together with another molecular component called the α-ketoadipate dehydrogenase (α-KADH) complex, adds the H4K91glu mark. The mark is removed by the enzyme SIRT7.
The researchers noted that the findings from this study lay the foundation for understanding human health and disease. They suggest that the new histone mark will open opportunities for the development of therapeutic agents to treat human diseases associated with misregulation of histone modification and chromatin structure.
The article can be found at: Bao et al. (2019) Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics.
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Source: University of Hong Kong; Photo: Shutterstock.
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