In eukaryotic nuclei, ~150 bp of DNA is wrapped around the histone octamer, which consists of two copies of four core histones (i.e., H2A, H2B, H3, and H4) to form a nucleosome, the fundamental unit of chromatin. Post-translational modifications on these histones play a critical role in genome function, including the regulation of transcription and the maintenance of genome integrity [1]. Since H3 and H4 are more stably integrated into nucleosomes compared to H2A and H2B , the modifications on H3 and H4 can act as long-term memory of epigenetic regulation[2].

Histone H3 has been the most extensively modified post-translationally among all histones . Thirteen acetylated K residues have been identified in human histone H3 , according to the CPLM 4.0 database[3],including K4, K9, K14, K18, K23, K27, K36, K37, K56, K64, K79, K115 and K122. Most of them were reported to have an impact on patients' outcomes in different cancer types[4]. Notably, in Eukaryotes, histone variants exist, with several variants for histone H3 identified in humans. These are categorized into canonical variants (H3.1 and H3.2) and replacement variants (H3.3, CENP-A, H3t, H3.X, and H3.Y). H3.1, H3.2 and H3.3 are the most prevalent variants, sharing a high degree of sequence similarity (over 96% for H3.1/H3.2 vs. H3.3, and over 99% for H3.1 vs. H3.2). These variants may, therefore, have similar PTMs on conserved amino acid residues. However, H3.1 and H3.2 are found predominantly in heterochromatin, while H3.3 is associated with euchromatin [5].

Modifications on histone H4 are also known to be involved in gene regulation and genome maintenance [6]. Lysine residues in H4 N-terminal tail (i.e., H4K5, H4K8, H4K12, and H4K16) are major acetylation sites . These acetylations are predominantly associated with euchromatin, contributing to chromatin decondensation and transcriptional regulation . H4K16ac is also known to be associated with DNA damage repair and cell senescence. In addition, H4K5ac and H4K12ac are associated with newly assembled chromatin since H4 in predeposition complexes is diacetylated at K5 and K12 by a histone acetyltransferase (HAT)[7]. Although the diacetylation of H4 is not a prerequisite for histone assembly, these modifications may stimulate nuclear import and contribute to the recovery from replication block-mediated DNA damage. After being assembled into chromatin, H4 becomes deacetylated in heterochromatin . In contrast to these four lysines that are acetylated, H4 lysine 20 (H4K20) is subject to methylation[8] . Monomethylation of H4K20 (H4K20me1) may play multiple roles in genome regulation, including transcriptional control, DNA replication licensing, DNA damage response, and chromosome segregation . Dimethylation of H4K20 (H4K20me2) is one of the most abundant modifications in mouse fibroblasts and HeLa cells, and is involved in DNA damage repair signaling [9].