Ubiquitin (Ub) is a highly conserved 76-amino acid protein that plays a critical role in regulating a wide range of cellular processes. Through a three-step process involving Ub-activating (E1), Ub-conjugating (E2), and Ub-ligating (E3) enzymes, ubiquitin covalently attaches to target proteins and marks them for proteasomal degradation, alters protein-protein interactions, modulates membrane protein trafficking, and controls the activity of many signal transduction pathways. Mono-ubiquitination of Histone H2B at Lys120 (H2BK120ub) serves signaling purposes and is reversible by ubiquitin-specific proteases (USPs). The enzymes responsible for H2BK120ub are Rad6 E2 proteins (HR6A and HR6B in human) and Bre1 E3 ligase (RNF20 and RNF40 in human). This modification triggers a “trans-histone” modification cascade, resulting in trimethylation of Lys4 and Lys79 in histone H3, which promotes gene activity.
Histone H3.3 is a histone H3 variant that replaces conventional H3 in a wide range of nucleosomes in active genes. Constitutes the predominant form of histone H3 in non-dividing cells and is incorporated into chromatin independently of DNA synthesis. Deposited at sites of nucleosomal displacement throughout transcribed genes, suggesting that it represents an epigenetic imprint of transcriptionally active chromatin. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
Histone post-translational modifications (PTMs) are key mechanisms of epigenetics that modulate chromatin structures, termed as “histone code”. The PTMs on histone including acetylation, methylation, phosphorylation and novel acylations directly affect the accessibility of chromatin to transcription factors and other epigenetic regulators, altering genome stability, gene transcription, etc. Histone acetylation occurs primarily at multiple lysine residues on the amino-terminal of core histones, in response to various stimuli and plays vital roles in the regulation of gene expression, DNA damage repair, chromatin dynamics, etc. Mostly, histone H2A is primarily acetylated at Lys5, 9, 15, and 36; H2B is primarily acetylated at Lys5, 12, 15, 16, and 20. Histone H3 is primarily acetylated at Lys4, 9, 14, 18, 23, 27, 56, and 79. Histone H4 is primarily acetylated at Lys5, 8, 12, 16, and 20. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are major regulating factors.
Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. This structure consists of approximately 146 bp of DNA wrapped around a nucleosome, an octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H3 family. Transcripts from this gene lack polyA tails; instead, they contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6p22-p21.3.
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