Histone Variants

1. What Are Histone Variants?

Histone variants are nonallelic isoforms of core histones and replace their canonical histone counterparts at strategic locations in the genome. Histone variants differ from core histones varying from minor alterations in amino acids to substantial structural differences. Canonical histones are typically synthesized during genome replication with peak expression in S-phase, whereas histone variants are expressed across the cell cycle and incorporated into chromatin in a replication-independent manner. Some histone variants exhibit tissue-specific expression, with restriction to germ cells.

Typically, eukaryotic genomes house replication-coupled (RC) histones in large multi-copy arrays, while histone variants are found in limited quantities, often as a single or just a few copies. Although histone variants share similarities with their RC histone counterparts, they exhibit distinct characteristics in their histone-fold domains (HFDs), setting them apart in terms of sequence and function.

Additionally, histone variants frequently display more significant differences from RC histones in their N- and C-terminal tails. These distinctions result in their association with different chaperones for deposition and the imposition of distinct post-translational modifications. As a consequence, these variations endow histone variants with specialized functions through alteration in chromatin properties ^[4,5].

2. Classifications of Histone Variants

All histones can exist as variants, but the diversification of replication-coupled (RC) histones into histone variants is not uniform. In the case of mammals, there are many H2A variants, a relatively smaller number of H3 variants, and even fewer H2B and H4 variants. This uneven diversification could be linked to the position of each histone within the nucleosome and its potential to modify nucleosome properties upon substitution.

Table 1. Mammalian histone variants.

The Table information is cited from: https://www.sciencedirect.com/science/article/pii/S0022283620305866 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015243/

Figure 1. Properties of Histone Variants

3. Function of Histone Variants

Histone variants affect nucleosome stability and higher-order chromatin organization by impacting histone post-translational modifications and the recruitment of histone variant-specific binding partners ^[3,6]. Histone variants play pivotal roles in nearly all DNA-templated processes, such as DNA repair, chromosome segregation, transcription regulation, genome stability, epigenetic inheritance, and even tissue-specific functions ^[2,3].

For instance, the centromere-specific variant centromeric protein A (CENP-A) serves as an epigenetic marker for the centromeric region of chromosomes, while H3.3 is closely linked to chromatin dynamics and nucleosome turnover. Moreover, numerous distinct H2A variants are involved in DNA repair, gene regulation, and other critical processes, thus affecting DNA organization. Therefore, the dysregulation of histone variant expression and deposition would lead to developmental syndromes and cancer.

4. Histone Variants and Diseases

Since histone variants have universal expression and pleiotropic effects, it is not surprising that they are implicated in normal physiology and many diseases, including developmental diseases and cancer. For instance, since histone variants may be the sole source of new histones in post-mitotic terminally differentiated tissues, such as the brain, histone variants may contribute significantly to brain-associated diseases, such as neurodevelopmental and neurodegenerative diseases. In fact, some studies suggest that the H3.3 and H2A.Z variants are essential for brain function ^[7-9].

In addition, given that many histone variants are testis-specific, replacement or modification of testis-specific histone variants might lead to male infertility ^[10].

It is known that many cancers and developmental syndromes carry recurrent mutations in genes encoding chromatin-related proteins, including histone variants and their deposition-specific partners. Studies have shown that mutations in H3.3 are frequently observed in pediatric gliomas and chondroblastomas ^{[11, 12]}. H2A.Z are demonstrated to exert oncogenic functions, while macroH2A and H2A.X inhibit tumorigenesis. Upregulation of H2A.Z is found in prostate and bladder cancer ^{[13, 14]}. The expression of MacroH2A declines as melanoma, bladder cancer, and anal neoplasms advance in disease progression ^{[15, 16]}.