Histone variants are the histone proteins with structural and sequence variations. These variants may be regarded as “mutant” forms that replace their canonical histone counterparts in the nucleosomes. Specific post-translational modifications on the histone variants enable further chromatin complexity and regulate tissue-specific gene expression. The most common histone variants are from histone H2A, H2B, and linker histone H1 families. However, several variants of histone H3 variants are also increasingly being studied.

Histone H3 variant: CENP-A

Centrosomal chromatin contains a specialized histone protein called CENP-A which shares 60% similarity with canonical histone H3. It is essential for kinetochore assembly and subsequent binding of microtubules. It is also hypothesized that CENP-A acts as an epigenetic mark to maintain centromere identity. The CENP-A is recognized and targeted to centromere via the CENP-A targeting domain (CATD).

In vitro studies have shown that centromeric nucleosomes form octomers with two copies of CENP-A along with two copies of H2A, H2B and H4 histones. Nevertheless, new studies in different eukaryotes have led to several competing models for the structure of CENP-A containing nucleosomes. According to the hemisome model, the nucleosome contains only one copy of each histone, forming a tetramer. In addition, recent studies have shown that CENP-A nucleosomes are cell cycle-regulated. They exist as octamers in S-phase and as hemisomes during other phases of the cell cycle.

Deregulation of CENP-A functions is linked to chromosome instability and cancer. Several pieces of evidence indicate overexpression of CENP-A in colon cancer, adenocarcinoma, testicular germ cell tumors, breast cancer and hepatocellular carcinoma.