HKU scientists discover ‘signpost’ in chromatin maze

4 November 2019

University of Hong Kong chemical biologists, including Dr Karen Wing Yee Yuen (Croucher Fellowship 2008), have identified a histone mark that regulates chromatin structure during gene expression and DNA repair.

The mark, they explain, functions like a crucial signpost for navigating through an ever- shifting maze, where paths move and break apart; wide, straight roads curl and shrink into tight, winding tracks; and new roads appear from what used to be dead-ends. Various signs (e.g., “STOP”, “SLOW”, “ONE WAY” and “DO NOT ENTER”) are the only guides through this maze.

Each of our cells contains such a “maze” within its chromatin, located in the cell nucleus and comprising a mass of genetic material composed of DNA and proteins called histones that condense to form chromosomes during eukaryotic cell division. The “packaging” of the DNA and histones can be tighter or looser in different regions of chromatin. While loose packaging indicates an “active” or a gene “ON” region, tight compaction means a “silent” or a gene “OFF” region.

The chromatin also contains various “road signs” in the form of chemical modifications to histones (or histone marks) that indicate the active, inactive or damaged regions of the chromatin and give order to various chromatin-associated machineries in the regulation of gene expression, DNA replication and damage repair.

While some well-known chromatin ”road signs”, such as lysine acetylation (Kac) and methylation (Kme), have been well characterised, the biological meanings of many other “signs”, particularly newly identified histone marks, remain mysterious.

The HKU research team led by Dr David Xiang Li, Associate Professor from the Department of Chemistry, in collaboration with Yuen, from the School of Biological Sciences, and Dr Jason Wing Hon Wong, from the School of Biomedical Sciences, revealed a new fundamental mechanism by which a cell can make necessary changes in its chromatin structure in response to different DNA-associated processes, such as gene expression and DNA damage repair. The findings were recently published in Molecular Cell.

In a search for new chromatin “road signs”, the team discovered a novel histone mark, lysine glutarylation (Kglu) at histone H4, Lysine-91 (H4K91glu) from human cells. The team, which has spent over five years on the project, found that this mark is especially abundant in promoter regions of active, “open” chromatin where genes are highly expressed – equivalent to an “expressway” road sign in the maze.

The team also found this “sign” present in mouse, fly, worm, and even baker’s yeast cells, indicating it has been conserved in evolution.

Besides marking the active genomic region, H4K91glu directly contributes to the formation of a more accessible chromatin structure that facilitates gene expression. The team found that H4K91glu destabilises nucleosome, the basic repeating unit of chromatin, and leads to activation or “opening” of chromatin.

This is due to the chemistry involved, they explain. The mark puts a negative charge on an originally positively charged lysine residue, causing a charge-charge repulsion within the nucleosome and making it more prone to falling apart.

Much like the ever-shifting maze, chromatin packaging is highly dynamic. A compacted region of chromatin can quickly change to a relaxed one, which allows fast switching between gene ON and OFF states. Meanwhile, when chromatin structure is changed at a specific region, the old “road signs” (i.e. histone marks) are taken off and new ones installed by enzymes called histone mark “erasers” and “writers”, respectively.

“To understand a histone mark, it is key to find its ‘writer’ and ‘eraser’,” said Li, whose team further identified the enzymes that “write” and “erase” the H4K91glu mark. KAT2A, working together with the α-ketoadipate dehydrogenase (α-KADH) complex, adds the H4K91glu mark, while SIRT7 works to remove it.

The researchers went on to demonstrate that H4K91glu must be removed by SIRT7 so that the open chromatin region could be inactivated and condensed during cell division or at a local DNA damage site.

Identifying H4K91glu as a novel histone mark and unravelling its regulation and function in chromatin structure and dynamics puts scientists one step closer to deciphering the chromatin maze.

The findings also lay the foundation for understanding how this novel histone mark contributes to human health and disease, opening up opportunities for development of therapeutic agents for the treatment of human diseases associated with mis-regulation of histone H4K91glu and chromatin structure.

Karen W. Y. Yuen completed her PhD in the Department of Medical Genetics at the University of British Columbia, Canada, studying chromosome instability in the budding yeast Saccharomyces cerevisiae and human cancers. She then pursued her post-doctoral training at the Ludwig Institute for Cancer Research and the University of California, San Diego, USA, studying centromere and kinetochore formation and propagation in Caenorhabditis elegans. Dr Yuen is currently an Assistant Professor in the School of Biological Sciences at the University of Hong Kong, and a recipient of the Hong Kong Research Grants Council Early Career Award. Karen received her Croucher Fellowship in 2008.

To view Dr Yuen’s Croucher profile, please click here.