Histones: Structure, Function & Diseases

Histones are a component of cell nuclei. Their presence is a distinguishing feature between unicellular organisms (bacteria) and multicellular organisms (humans, animals, or plants). Only a very few bacterial strains possess proteins that are similar to histones. Evolution has produced histones in order to better and more effectively accommodate the very long DNA chain, also called genetic material, in the cells of higher organisms. This is because if the human genome were wound apart, it would be about 1-2 m long in total, depending on which cell stage a cell is in.

What are histones?

In more highly developed organisms, histones are found in the nuclei of cells and are high in positively charged amino acids (mainly lysine and arginine). Histone proteins are divided into five main groups – H1, H2A, H2B, H3, and H4. Between different organisms, the amino acid sequences of the four groups H2A, H2B, H3, and H4 differ little, while more differences exist for H1, a linking histone. In the nucleated red blood cells of birds, H1 is even completely replaced by another major histone group, called H5. The high degree of sequence similarity in most histone proteins means that in most organisms the “packaging” of DNA occurs in the same way, and the resulting three-dimensional structure is equally effective for histone function. Thus, in the course of evolution, the development of histones must have occurred very early and been maintained in this way, even before mammals or humans evolved.

Anatomy and structure

Once a new DNA chain of individual bases (called nucleotides) is formed in a cell, it must be “packaged.” To do this, histone proteins dimerize, each of which then forms two tetramers. Finally, a histone core consists of two tetramers, the histone octamer, around which the DNA strand wraps and partially penetrates. Thus, the histone octamer is in the three-dimensional structure within the coiled DNA strand. The eight histone proteins with the DNA around them form the overall complex of a nucleosome. The DNA region between two nucleosomes is called linker DNA and comprises about 20-80 nucleotides. Linker DNA are responsible for the “entry” and “exit” of DNA into the histone octamer. Thus, a nucleosome consists of approximately 146 nucleotides, a linker DNA portion, and eight histone proteins, such that the 146 nucleotides wrap around the histone octamer 1.65 times. Further, each nucleosome is associated with an H1 molecule, so that the entry and exit sites of the DNA are held together by the linker histone, increasing the compactness of the DNA. A nucleosome is about 10 -30 nm in diameter. Many nucleosomes form chromatin, a long DNA-histone chain that looks like a string of beads under the electron microscope. The nucleosomes are the “beads” that are surrounded or connected by the string-like DNA. Quite a few non-histone proteins support the formation of the individual nucleosomes or the entire chromatin, which finally forms the individual chromosomes when a cell is to divide. Chromosomes are the maximum type of condensation of chromatin and are visible by light microscopy during nuclear division of a cell.

Function and tasks

As mentioned above, histones are basic proteins with a positive charge, so they interact with negatively charged DNA by electrostatic attraction. The DNA “wraps around” the histone octamers in such a way that the DNA becomes more compact and fits into the nucleus of each cell. In this process, the H1 has the function of compacting the superordinate chromatin structure and usually prevents transcription and thus translation, i.e. the translation of this DNA portion into proteins via an mRNA. Depending on whether the cell is “resting” (interphase) or dividing, the chromatin is less or more condensed, i.e. packed. In interphase, large portions of chromatin are less condensed and can therefore be transcribed into mRNAs, i.e. read and later translated into proteins. Thus, histones regulate the gene activity of individual genes in their vicinity and allow transcription and the formation of mRNA strands. When a cell enters cell division, the DNA is not translated into proteins, but is distributed evenly between the two daughter cells that are formed. Therefore, the chromatin is highly condensed, and additionally stabilized by the histones.The chromosomes become visible and can be distributed to the newly forming cells with the help of many other non-histone proteins.

Diseases

Histones are essential in the formation of a new living being. If, due to mutations in the histone genes, one or more of the histone proteins cannot be formed, that organism is not viable and further development is terminated prematurely. This is mainly due to the high sequence conservation of histones. However, it has been known for some time that in children and adults with various malignant brain tumors, mutations can occur in the various histone genes of the tumor cells. Especially in so-called gliomas, mutations in the histone genes have been described. Also, elongated chromosome end pieces have been discovered in these tumors. These, called telomeres, end sections of the chromosomes are normally responsible for the longevity of the chromosomes. In this context, it appears that the elongated telomeres in the tumors with histone mutations give these degenerate cells a survival advantage. Meanwhile, other types of cancer are known to have mutations in the various histone genes and thus produce mutated histone proteins that do not perform their regulatory tasks or do so only poorly. These findings are currently being used to develop forms of therapy for particularly malignant and aggressive tumors as well.