The genetic material inside the nucleus of every eukaryotic cell is deoxyribonucleic acid (DNA). If the DNA from a single human cell were stretched out, it would measure approximately 1.8 meters in length. To solve this packaging problem, the cell tightly coils and wraps the DNA around specific proteins. This complex of DNA and protein is called chromatin, and its basic, repeating structural unit is the nucleosome. The nucleosome acts as a spool, allowing the immense length of the genome to be compactly stored and regulating access to the genetic code.
The Core Histone Octamer
The precise answer to how many histone proteins are in the core of a nucleosome is eight, forming a structure known as the histone octamer. These eight proteins represent two copies each of four types of core histones: H2A, H2B, H3, and H4. The octamer is a highly conserved, positively charged protein complex that binds tightly to the negatively charged DNA molecule.
The assembly of this complex occurs sequentially. First, two copies of the H3 histone and two copies of the H4 histone form an H3/H4 tetramer in the center. Subsequently, two separate dimers, each consisting of one H2A and one H2B histone, associate with the central H3/H4 tetramer to complete the eight-protein octamer. Each of these four core histone types contains a characteristic structural element called the histone-fold domain, which facilitates the necessary protein-to-protein interactions.
The positive charge of the histone proteins is largely due to a high content of the amino acids lysine and arginine, allowing for a strong electrostatic attraction to the phosphate backbone of the DNA. This effectively neutralizes the DNA’s charge and allows it to be condensed by an estimated 10,000-fold. The core histones also possess N-terminal tails that protrude outward from the central octamer, playing a role in inter- and intra-nucleosomal interactions that influence gene accessibility.
DNA Wrapping and Nucleosome Structure
Approximately 146 to 147 base pairs of DNA are wrapped around the exterior of the histone core particle. This DNA segment completes about 1.65 to 1.67 left-handed superhelical turns around the protein spool.
The coiling of the DNA around the octamer creates a disk-shaped particle with a diameter of about 11 nanometers. The binding is maintained through a series of weak interactions, including hydrogen bonds and salt bridges, between the DNA’s phosphate backbone and the histone proteins. This loose but stable association allows the DNA to be repositioned or separated from the histones by cellular machinery when gene expression or DNA replication is required.
The histone core interacts with the DNA at multiple points, particularly where the DNA’s minor groove faces the protein octamer. The core histones, through their histone-fold domains, interact with the minor groove of the DNA. This precise wrapping is the first level of DNA compaction.
The Role of the Linker Histone
The nucleosome complex often includes a fifth histone known as the linker histone, most commonly H1. While H1 is not part of the eight-protein core octamer, it is an integral component of nucleosome structure and function. This protein binds to the stretch of DNA where it enters and exits the core particle, acting like a clasp to stabilize the entire assembly.
The binding of H1 protects an additional 15 to 30 base pairs of DNA located in the linker region between adjacent nucleosomes. H1 helps to lock the DNA in place, preventing it from unwinding too easily from the core octamer. The presence of H1 creates a structure called the chromatosome, which consists of the nucleosome core particle plus the H1-protected linker DNA.
Building Higher-Order Chromatin
The formation of individual nucleosomes results in a structure often described as “beads on a string.” These nucleosomes are connected by stretches of linker DNA, forming a fiber that is approximately 10 nanometers in diameter. This 10 nm fiber is the substrate for the next major level of organization.
The linker histone H1 is essential for organizing this 10 nm fiber into a more condensed structure known as the 30 nanometer fiber. The H1 protein facilitates the folding of the nucleosome array, promoting inter-nucleosome interactions for the formation of a thicker, more compact fiber. This higher-order compaction significantly reduces the volume of the genetic material.
Although the exact structure of the 30 nm fiber remains debated, with models suggesting either a solenoid or a zigzag arrangement, its formation is directly dependent on the presence of the linker histone. The condensation into the 30 nm fiber and subsequent folding into even larger structures is essential for preparing the DNA for cell division and regulating the accessibility of genes to the cellular machinery.