Histone

Histones are crucial proteins found in chromatin, playing a fundamental role in the structure and packaging of DNA in eukaryotic cells. There are five primary histones found in most eukaryotic species: H1, H2A, H2B, H3, and H4. These small, basic proteins possess an abundance of lysine and arginine residues, allowing them to bind to the negatively charged sugar-phosphate backbone of DNA.

The structure of chromatin is heavily influenced by histones. When treated with a low ionic strength solution, chromatin unfolds, revealing a bead-like appearance under electron microscopy. These "beads" are nucleosomes, each composed of one molecule of histone H1 and two molecules each of histones H2A, H2B, H3, and H4, together with approximately 200 base pairs of DNA. The H2A, H2B, H3, and H4 histones form an octamer around which DNA wraps, with about 146 base pairs of DNA forming the nucleosome core particle, and an additional 54 base pairs as linker DNA.

1.0Overview of DNA Packaging Diagram 

2.0Types of histones in octamer

1. Histone H2A

H2A is the core histone with the largest number of variants. The histone H2A variants include H2AZ and H2AX, which are found in most eukaryotes, and H2A. Bbd and MacroH2A are only found in vertebrates. The H2A histone variants are characterized by their divergent C- terminal sequences and their genome localization. H2AZ has been implicated in transcriptional activation in yeast by preventing the spread of silent heterochromatin. H2ABbd was recently described as a histone variant that is excluded from inactive X chromosomes .H2ABbd has a truncated C-terminal tail and its localization correlates with transcriptionally active chromatin. Recent studies measured changes in nucleosome conformation as a function of variations in ionic strength, indicating that nucleosomes containing H2ABbd are less stable. On the contrary, the MacroH2A histone variant has been found primarily in the chromatin of inactive X chromosomes characterized by the presence of an additional large nonhistone macrodomain that is likely to have enzymatic activity. However, it is not clear

if chromatin inactivation is due to an enzymatic activity and/or a steric block that impedes access by transcription factors or the chromatin remodeling machinery [44]. H2AX is characterized by a C-terminal extension with the consensus SQ[E/D]Φ, where Φ represents a hydrophobic amino acid. The serine residue in the consensus is phosphorylated in response to double-strand DNA breaks . Additionally, phosphorylation of H2AX has been found to aid in the recruitment of proteins involved in DNA repair.

2. Histone H2B

Histone H2B variants are few in number and those that have been documented have specialized roles in chromatin compaction during gametogenesis. The H2B variant documented in sea urchin has an N-terminal tail with a characteristic pentapeptide repeat that is highly charged. Additional H2B variants have also been found in male gametic cells from lily and, more recently, in bovine and human spermatozoa , however, their specific roles remain to be elucidated.

3. Histone H3

Histone H3 variants include H3, CenHS and H3. H3 is a histone variant that is not S-phase regulated and is found in transcriptionally active chromatin. H3.4 is a testis-specific H3 variant found in primary spermatocytes. The CenH3 variant is localized in centromeric chromatin; their N-terminal tails are extremely divergent and share no sequence similarity with canonical H3.

4. Histone H4

Histone H4 is the most highly conserved histone. H4 makes extensive contacts with the other three core histones in the nucleosome core particle and is thus constrained in its sequence variability. H4 has no known sequence variants; indeed, there are even identical sequence variants that are expressed in a cell cycle-independent manner as opposed to the predominant synthesis period for histones in the S phase of the cell cycle.

3.0Types of Histone Modification

Chromatin architecture, nucleosomal positioning, and ultimately access to DNA for gene transcription, is largely controlled by histone proteins. Each nucleosome is made of two identical subunits, each of which contains four histones: H2A, H2B, H3, and H4. Meanwhile, the H1 protein acts as the linker histone to stabilize internucleosomal DNA and does not form part of the nucleosome itself.

Histone proteins undergo post-translational modification (PTM) in different ways, which impacts their interactions with DNA. Some modifications disrupt histone-DNA interactions, causing nucleosomes to unwind. In this open chromatin conformation, called euchromatin, DNA is accessible to binding of transcriptional machinery and subsequent gene activation. In contrast, modifications that strengthen histone-DNA interactions create a tightly packed chromatin structure called heterochromatin. In this compact form, transcriptional machinery cannot access DNA, resulting in gene silencing. In this way, modification of histones by chromatin remodeling complexes changes chromatin architecture and gene activation.

At least nine different types of histone modifications have been discovered. Acetylation, methylation, phosphorylation, and ubiquitylation are the most well-understood, while GlcNAcylation, citrullination, krotonilation, and isomerization are more recent discoveries that have yet to be thoroughly investigated. Each of these modifications are added or removed from histone amino acid residues by a specific set of enzymes.

Chromatin architecture, nucleosomal positioning, and ultimately access to DNA for gene transcription, is largely controlled by histone proteins. Each nucleosome is made of two identical subunits, each of which contains four histones: H2A, H2B, H3, and H4. Meanwhile, the H1 protein acts as the linker histone to stabilize internucleosomal DNA and does not form part of the nucleosome itself.

Histone proteins undergo post-translational modification (PTM) in different ways, which impacts their interactions with DNA. Some modifications disrupt histone-DNA interactions, causing nucleosomes to unwind. In this open chromatin conformation, called euchromatin, DNA is accessible to binding of transcriptional machinery and subsequent gene activation. In contrast, modifications that strengthen histone-DNA interactions create a tightly packed chromatin structure called heterochromatin. In this compact form, transcriptional machinery cannot access DNA, resulting in gene silencing. In this way, modification of histones by chromatin remodeling complexes changes chromatin architecture and gene activation.

At least nine different types of histone modifications have been discovered. Acetylation, methylation, phosphorylation, and ubiquitylation are the most well-understood, while GlcNAcylation, citrullination, crotonylation, sumoylation, and isomerization are more recent discoveries that have yet to be thoroughly investigated. Each of these modifications are added or removed from histone amino acid residues by a specific set of enzymes.

4.0Structure of Histone Octamer 

X-ray crystallography has revealed the structure of the nucleosome core particle. This core particle consists of eight histone subunits organized symmetrically as four dimers: two H2A/H2B dimers and two H3/H4 dimers. It forms a disc-shaped structure with positively charged grooves that accommodate the DNA's sugar-phosphate backbone.

The nucleosome comprises an octamer of histone proteins, including two copies each of H2A, H2B, H3, and H4, around which approximately 146 base pairs of DNA are wound. The histone H1 is associated with the linker DNA, connecting adjacent nucleosomes.

The N-terminal of the core histones, rich in positively charged lysine (K) and arginine (R) residues, extend outward from the core particle, interacting with DNA and other proteins' negatively charged regions. These interactions help stabilize higher-order chromatin structures, such as the 30 nm fiber.

The coiling and packaging of DNA around these histone core particles significantly impact the overall structure of chromatin, demonstrating the crucial role histones play in organizing and regulating DNA within the cell.

5.0Diagram of Histone Octamer