While any new study mentioning histones generally gets our epigenetic tails wagging, a stunning study into how cancer-associated histone mutations influence nucleosome remodeling has also got our “globular” bodies moving! Although most researchers focus on mutations in the histone tail, most high-frequency cancer-associated mutations actually affect the main “bodies” of the histone proteins (known as globular domains) and remain largely uncharacterized.
To assess the biochemical and cellular effects of cancer-associated mutations affecting both histone globular domains and tails, researchers led by C. David Allis (Rockefeller University, New York) and Tom W. Muir (Princeton University, New Jersey) recently took advantage of two complementary tools – a DNA-barcoded mononucleosome library for high-throughput biochemical evaluations using next-generation sequencing and a yeast library of strains carrying human histones for phenotypic evaluations.
So, what details of this study linking cancer-associated histone mutations, nucleosome remodeling, and gene expression alterations from Bagert and colleagues got our epigenetic bodies moving and tails wagging?
- Cancer-associated histone mutations affecting the globular domain of histones prompt increases in histone dimer exchange, decreases in the thermal stability of nucleosomes, and significant growth defects in yeast
- These mutations also induce significant alterations to nucleosome remodeling
- While mutations affecting histone-DNA contact sites promote nucleosome remodeling, mutations within the nucleosome-binding interfaces reduce or even abolish this activity
- Mutations at residues associated with altered nucleosome remodeling also lead to defects in yeast growth, with mutations in nucleosome-binding interfaces particularly susceptible
- RNA-sequencing analysis in mesenchymal progenitor cells carrying cancer-associated mutations in the histone globular domain that affect nucleosome remodeling demonstrated significant alterations to gene transcription profiles associated with tumorigenesis, pluripotency, and fate determination
Overall, these exciting new findings suggest that cancer-associated mutations affecting the globular domains of histones can significantly impact nucleosome remodeling and get that histone body moving! Therefore, these previously under-appreciated mutations can significantly influence gene expression profiles and may promote the onset/development/progression of diseases such as cancer.
“We found mutations inside the core of the histones – in all four histones – and they seem to do completely different things than previously identified histone mutations,” said John Bagert, co-lead author and postdoc in the Muir Lab. “They affect the actual structure of the nucleosome itself and seem to destabilize it in some cases. These are fundamental processes that people studying chromatin think about all the time, but they have not been linked in this way to cancer previously. So, we think that mutations that affect chromatin remodeling can contribute to disease and cancers in humans. We’ve identified the sites and the mutations at those sites that we think are causing problems.”
For more on how this new research into cancer-associated histone mutations got our bodies moving and tails wagging, see Nature Chemical Biology, March 2021.