At
the cellular level, cancer is the disease of both the genome
and the epigenome, and the interplay between genetic mutations and
epigenetic states may occur at the level of elementary chromatin units,
the nucleosomes. They are formed by a segment of DNA wrapped around
an octamer of histone proteins. In this review, we survey various
mechanisms of cancer etiology and progression mediated by histones
and nucleosomes. In particular, we discuss the effects of mutations
in histones, changes in their expression and slicing on epigenetic
dysregulation and carcinogenesis. The links between cancer phenotypes
and differential expression of histone variants and isoforms are summarized.
Finally, we discourse the geometric and steric effects of DNA compaction
in nucleosomes on DNA mutation rate, interactions with transcription
factors, including pioneer transcription factors, and prospects of
cancer cells’ genome and epigenome editing.
Histones have a long history of research in a wide range of species, leaving a legacy of complex nomenclature in the literature. Community-led discussions at the EMBO Workshop on Histone Variants in 2011 resulted in agreement amongst experts on a revised systematic protein nomenclature for histones, which is based on a combination of phylogenetic classification and historical symbol usage. Human and mouse histone gene symbols previously followed a genome-centric system that was not applicable across all vertebrate species and did not reflect the systematic histone protein nomenclature. This prompted a collaboration between histone experts, the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC) and Mouse Genomic Nomenclature Committee (MGNC) to revise human and mouse histone gene nomenclature aiming, where possible, to follow the new protein nomenclature whilst conforming to the guidelines for vertebrate gene naming. The updated nomenclature has also been applied to orthologous histone genes in chimpanzee, rhesus macaque, dog, cat, pig, horse and cattle, and can serve as a framework for naming other vertebrate histone genes in the future.
Nucleosomes are basic building blocks of chromatin, comprising DNA wrapped around an octamer of eight histone proteins. They play key roles in DNA compaction, epigenetic mark up of the genome and actively participate in chromatin dynamics. X-ray and later cryo-EM studies have contributed greatly to our understanding of nucleosome structure, their interactions and dynamics. With over 470 nucleosome containing structures in the Protein Data Bank there is a wealth of information to be gleaned from these structures, especially through comparative analysis. However, due to the variability in their representation (chain naming, residue numbering, other artifacts), these structures cannot be systematically analyzed "as is". To address this issue, we developed a framework for analyzing and classifying nucleosome structures and their complexes, resulting in the creation of the NucleosomeDB database and the corresponding web-service. NucleosomeDB allows researchers to search, explore, and compare nucleosomes with each other, despite differences in composition and peculiarities of their representation. By utilizing the information contained within the NucleosomeDB, researchers can gain valuable insights into how nucleosomes interact with DNA and other proteins, assess the implications of mutations and protein binding on nucleosome structure. The detailed information contained within NucleosomeDB can contribute to a better understanding of the structure and function of nucleosomes, and ultimately, the functioning of chromatin and gene regulation. NucleosmeDB is freely available at https://nucldb.intbio.org.
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