Chromatin structure, nucleosome positioning, and ultimately DNA acquisition for gene transcription, are largely controlled by histones. Each nucleosome consists of two identical subunits, each containing four histones: H2A, H2B, H3, and H4. At the same time, the H1 protein acts as a linker histone to stabilize DNA between nucleosomes and does not form part of the nucleosome itself.
Histones undergo post-translational modifications in different ways, which affect their interaction with DNA. Some histone modifications disrupt histone-DNA interactions, leading to nucleosome unwinding. In this open chromatin conformation called euchromatin, DNA can bind to the transcription machinery and subsequently activate genes. In contrast, modifications that enhance histone-DNA interactions create a tightly packed chromatin structure called heterochromatin. In this compact form, the transcription machinery does not have access to the DNA, resulting in gene silencing. In this way, histone modifications by chromatin remodeling complexes alter chromatin structure and gene activation.
At least nine different types of histone modifications have been identified. Acetylation, methylation, phosphorylation, and ubiquitination are the most well-understood, while GlcNAcylation, citrullination, krotonilation, and isomerization are recent discoveries that have yet to be thoroughly studied. Each of these modifications is added or removed from histone amino acid residues by a specific set of enzymes.
Together, these histone modifications constitute the so-called histone code, which determines the transcriptional state of local genomic regions. Examining histone modifications in specific regions or the entire genome can reveal the state of gene activation and the location of promoters, enhancers, and other gene regulatory elements.
Acetylation is one of the most widely studied histone modifications, as it was one of the first modifications identified to affect transcriptional regulation. Acetylation adds a negative charge to lysine residues in the N-terminal histone tails that protrude from the nucleosome. These negative charges repel negatively charged DNA, resulting in the relaxation of chromatin structure. An open chromatin conformation allows transcription factor binding and dramatically increases gene expression.
Histone acetylation is involved in cell cycle regulation, cell proliferation, and apoptosis, and may play important roles in regulating many other cellular processes, including cell differentiation, DNA replication and repair, nuclear import, and neuronal inhibition. Imbalances in the balance of histone acetylation are associated with tumorigenesis and cancer progression.