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DNA is a two-stranded molecule that carries all our genetic information in the form of a code made up of four bases arranged in specific sequences. DNA has its own section of the cell, the nucleus, which serves to protect and contain it. As the cell divides and the DNA replicates, sometimes mistakes are made in the copy, called mutations. Not all mutations are harmful, but mutations in certain genes, often referred to as oncogenes, can potentially cause cancer. Moreover, cancer can also be caused by certain alterations to how genes are expressed. And one example of such mutation affects how the DNA is organized in cells.
DNA itself is meters long, far longer than the human body, so in order to be able to fit inside a cell’s nucleus, which is a thousand times smaller, it is condensed and wrapped around nuclear proteins, called histones. This compacted DNA-protein complex is known as chromatin, and the repeating subunit of chromatin, which is like a bead on a string, is called the nucleosome. Histones are the main protein components of chromatin that help with packaging the DNA, and within each nucleosome, DNA winds around an eight-protein complex, consisting of two copies each of the four core histone proteins, one of which is histone H3.
Both nucleosomes and histones can be modified to control their function. Nucleosomes can be moved, ejected, or restructured by chromatin remodeling complexes. Meanwhile, histones can be modified by specific enzymes that usually either add or remove different chemical groups to these histones. An example of one such modification is methylation, where a methyl (CH3) group is added to the histone. All these modifications affect whether chromatin is loosely or very tightly packed, which in turn affects how accessible the DNA is to biomolecules that help convert genes into proteins, like transcription factors and other DNA binding proteins. Therefore, it can be said that chromatin structure plays an important role in regulating transcription and ultimately gene expression, which control cellular behavior.
Because of chromatin’s important role in gene expression, these histone-modifying enzymes and chromatin remodeling complexes are vital for normal cellular development and can be altered in diseases such as cancer. Mutations can even occur in the genes of histones themselves, particularly histone H3 genes. These mutations involve the substitution of an amino acid with a different amino acid in the proteins, which change how the histone interacts with DNA. Mutant histones that are linked to cancer development are named oncohistones.
Mutations in histone H3 genes were previously found in various pediatric cancers, including pediatric glioblastomas (malignant tumors affecting the brain or spinal cord), chondroblastomas (rare bone tumors seen mostly in children and adolescents), and giant cell tumors of bone, or GCTBs (relatively common bone tumors seen in early adulthood). These mutations occur at very high frequencies and, when present, are often much more strongly expressed than normal versions of these genes. Remarkably, histone mutations are highly specific to the type of tumor, as well as the tumor’s location in the body. In other words, each mutation will only be found in tumors of a specifically defined anatomical site.
One example of an oncohistone is the H3K27M mutation, where a methionine residue replaces the amino acid residue 27 of histone H3, which is originally a lysine. Lysine is a positively charged amino acid, while methionine is uncharged; this substitution therefore changes the way it interacts with itself and its environment. This mutation has been identified in 78% of diffuse intrinsic pontine gliomas (highly aggressive tumors found at the base of the brain) and remains in tumors all throughout the stages of cancer. Normal histone H3 can be tri-methylated (three methyl groups are added to the histone) at amino acid 27, which leads to tighter chromatin packing and reduced gene expression. But with this one H3K27M mutation, levels of tri-methylation of amino acid 27 are reduced, both in the mutated histone and in other histone H3 proteins throughout the chromatin, resulting in a reduction of transcriptional silencing.
Targeted therapies are being developed and tested in cells (in vitro) and in animals (in vivo) to try to combat the effects of these harmful histone mutations. For example, one study observed that inhibiting deacetylases (enzymes that remove methyl groups from histones) in H3K27M mutant cells did increase trimethylation levels even if the histone mutation itself is still being expressed. However, further studies would need to be done to clarify if the inhibitor is specific to this particular histone deacetylase or if it affects all histone deacetylases, leading to undesirable gene expression levels.
In addition, a research team led by Dr. David Allis has performed genomic analyses of tumor sequencing databases and has revealed that there is actually a lot more information about oncohistones available than previously thought, although much remains to be discovered. For instance, they have identified histone mutations in about 4% of assorted tumor types, many of which have not previously been recognized as significant. This percentage of occurrence is about the same as that of other, better known cancer-causing mutations. They have also seen that these mutations occur in all four of the core histones, not just histone H3. And with their analyses, they have been able to hypothesize further possible roles of oncohistones in tumor growth and progression.
We still have a lot to learn about these oncohistones, but with the ongoing development of therapies targeting histone mutations and with the expanding knowledge on oncohistones, we are one step closer to understanding the true extent of the damage in altering these histone protein components and how this leads to cells becoming cancerous.
Edited by Sara Musetti
Mohammad, F. and Helin, K. (2017). Oncohistones: drivers of pediatric cancers. Genes & Development, 31, 2313-2324. doi: 10.1101/gad.309013.117.
Nacev, B.A., Feng, L., Bagert, J.D., Lemiesz, A.E., Gao, J., Soshnev, A., Kundra, R., Schultz, N., Muir, T.W., and Allis, C. D. (2019). The expanding landscape of “oncohistone” mutations in human cancers. Nature, 567(7749), 473-478. doi: 10.1038/s41586-019-1038-1.
Cover Image: DNA Wrapped Around Histones
Figure 1 was designed by the author from the following sources: