Histone H3 Modifications: The Silent Conductors in the Cellular Symphony

Histone H3 is one of the core components of nucleosomes. It interacts with histones H2A, H2B, and H4 through non-covalent bonds to form an octameric complex, which compacts DNA into nucleosomes. Nucleosomes serve as the fundamental structural units of chromatin.

Figure 1: Structure of a Nucleosome

Histone H3 has a theoretical molecular weight of approximately 15 kDa and is localized in the nucleus. It is expressed in most tissues, primarily during the S phase of the cell cycle, and its expression levels decrease sharply as cell division slows during differentiation.

Histone H3 plays a central role in transcriptional regulation, DNA repair and replication, and chromosomal stability. The accessibility of DNA is regulated through a complex series of post-translational modifications (also known as the histone code) and nucleosome remodeling.

Post-Translational Modifications

Histone H3 regulates DNA accessibility through a series of post-translational modifications (histone code) and nucleosome remodeling. These modifications include acetylation, ubiquitination, phosphorylation, methylation, citrullination, succinylation, and isobutyrylation, among others. Modified Histone H3 can alter chromatin structure, influencing the accessibility of chromatin to transcription factors and thereby regulating gene expression. It plays a critical role in various biological processes, including but not limited to gene expression regulation, DNA repair, cell cycle control, cell proliferation and apoptosis, and neuronal inhibition.

Figure 2: Modifications of the N-terminal Tail Domain of Histone H3. Classic methylation, acetylation, and phosphorylation sites are indicated.

Key Modifications

Acetylation (Acetylation):

Acetylation is typically associated with gene activation, as it neutralizes the positive charge on histones, making DNA more accessible to the transcriptional machinery. Acetylation commonly occurs on lysine residues of H3, such as H3K9ac (acetylation of lysine 9 on Histone H3), H3K14ac, and H3K27ac.

Methylation (Methylation):

Methylation can occur on different lysine residues, with each methylation state potentially having distinct functions. For example, H3K4me3 (trimethylation of lysine 4 on Histone H3) is often associated with active transcription, while H3K27me3 is linked to gene silencing.

Phosphorylation (Phosphorylation):

Phosphorylation occurs on specific threonine and tyrosine residues and is associated with cell cycle progression, particularly chromosome condensation during mitosis and meiosis, and the DNA damage response. Examples include H3S10ph (phosphorylation of serine 10 on Histone H3) and H3T11ph.

Lactylation (Lactylation):

Histone H3 lactylation primarily occurs on lysine residues, with different sites of lactylation having distinct functional impacts. For instance, H3K18la (lactylation of lysine 18 on Histone H3) plays a role in various diseases, such as promoting ferroptosis through m6A modification of ACSL4 in sepsis-induced lung injury. H3K18la is also being studied as a potential biomarker for septic shock. H3K9la (lactylation of lysine 9 on Histone H3) is involved in regulating gene expression and disease progression, potentially influencing endothelial-mesenchymal transition (EndMT) in atherosclerosis.

Crotonylation (Crotonyl):

Crotonylation typically plays an important role in regulating gene expression and chromatin structure, primarily occurring on lysine residues. H3K23cr (crotonylation of lysine 23 on Histone H3) is associated with transcriptional regulation. The MORF complex has been identified as a specific H3K23 acetyltransferase, and this activity is linked to crotonylation at H3K14.

Total Protein and Other Modifications