Histones are fundamental proteins found within the nucleus of eukaryotic cells. These proteins are highly basic, due to amino acids like lysine and arginine. This positive charge allows them to associate with DNA, which carries a negative charge due to its phosphate groups. Histones’ proper organization and function are foundational for cell operation and survival.
DNA Super-Packers
Histones serve as the main components for packaging the vast amount of DNA within a cell’s nucleus. A single human cell’s DNA, if unwound, would stretch about 2 meters, fitting into a 6-micrometer nucleus. This feat of compaction begins with DNA wrapping around a core of eight histone proteins, forming a structure called a nucleosome. Each nucleosome core has two copies of four histone types: H2A, H2B, H3, and H4.
About 147 base pairs of DNA coil around this histone octamer, creating a “beads-on-a-string” appearance under a microscope. Another histone, H1, acts as a linker, binding where the DNA enters and exits the nucleosome, stabilizing the structure. These nucleosomes then coil and fold into higher-order structures, forming a more condensed fiber known as chromatin, roughly 30 nanometers in diameter.
During cell division, this chromatin undergoes further condensation, ultimately forming the distinct chromosomes. This packaging allows DNA to fit inside the nucleus, protects it from damage, and ensures proper segregation during cell division. Without histones, the extensive DNA strands would become tangled and susceptible to damage, hindering cellular processes and replication.
Orchestrators of Gene Activity
Histones are not just passive spools for DNA; they actively regulate gene expression, influencing gene activation or silencing. DNA wrapping around histones dictates its accessibility to cellular machinery for gene transcription. Regions of DNA tightly bound to histones are less accessible, leading to gene silencing, while loosely packed regions allow for active gene transcription.
This control is achieved through chemical modifications to histones, known as post-translational modifications. Common modifications include acetylation and methylation, occurring on specific amino acid residues like lysine and arginine within histone tails. For instance, histone acetylation, the addition of an acetyl group, neutralizes the positive charge of lysine residues, weakening the interaction between histones and the negatively charged DNA. This loosening of the DNA-histone interaction creates a more “open” chromatin structure, making genes in that region more accessible for transcription, promoting gene activity.
Conversely, histone methylation can have varied effects depending on the specific residue modified and the number of methyl groups added. Some methylation patterns activate genes, while others silence them by recruiting proteins that compact chromatin. These modifications create a complex “histone code” that cellular proteins interpret to regulate processes like DNA replication, repair, and overall gene expression, influencing cell identity and function.
When Histones Go Wrong
Dysfunctional histones or errors in their modifications can disrupt the balance of gene regulation, leading to cellular problems and diseases. The precise control over gene expression by histones is fundamental for cellular health and development. When this control is lost, genes can be inappropriately activated or silenced, contributing to disease progression.
For example, disruptions in histone modifications have been linked to certain cancers. Altered patterns of histone acetylation and methylation can lead to the activation of cancer-promoting genes or the silencing of tumor-suppressor genes, contributing to uncontrolled cell growth and proliferation. Specific mutations in enzymes that modify histones have been identified in various malignancies, including lymphomas and renal carcinomas.
Beyond cancer, errors in histone function or modification are also implicated in developmental disorders. Conditions like Weaver syndrome, characterized by overgrowth and intellectual disability, link to mutations in enzymes regulating histone methylation. Proper histone function is therefore important for maintaining genomic integrity and preventing diseases from gene misregulation.