Хромотин құрамындағы H4 гистонының құрылымы мен функциясы

One of the five main histone proteins involved in the structure of chromatin

Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N terminal tail, H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post translationally modified. Covalently bonded modifications include acetylation and methylation of the N terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer. Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.

Histone proteins are among the most highly conserved eukaryotic proteins. For example, the amino acid sequence of histone H4 from a pea and cow differ at only 2 out of the 102 positions. This evolutionary conservation suggests that the functions of histone proteins involve nearly all of their amino acids so that any change is deleterious to the cell. Most changes in histone sequences are lethal; the few that are not lethal cause changes in the pattern of gene expression as well as other abnormalities.

Histone H4 is a 102 to 135 amino acid protein which shares a structural motif, known as the histone fold, formed from three a helices connected by two loops. Histone proteins H3 and H4 bind to form a H3 H4 dimer, two of these H3 H4 dimers combine to form a tetramer. This tetramer further combines with two H2a H2b dimers to form the compact Histone octamer core. Variants in human histone H4 were only recently discovered and are very rare. Pathogenic de novo missense variants have been identified in six H4 genes (HIST1H4C, HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4I, HIST1H4J) in 33 individuals total, all presenting with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, but with variable non neurological features. Ten amino acids were affected, six of which were found recurrently. These mutations were located within either the H4 core globular domain (involved in protein protein interaction) or C terminal tail (involved in post translational modification). It is found in human and rat circulation as well as regenerating bone marrow. In blood serum it is bound to α2M along with two other binding proteins that are not clearly identified. A specific receptor has not been identified, but some signaling pathways involved in its bone regenaration function has been elucidated.

Eukaryotic organisms can produce small amounts of specialized variant core histones that differ in amino acid sequence from the main ones. These variants with a variety of covalent modifications on the N terminal can be added to histones making possible different chromatin structures that are required for DNA function in higher eukaryotes. Potential modifications include methylation (mono , di , or tri methylation) or acetylation on the tails. Histone methylation has been associated with various cellular functions such as transcription, DNA replication, and DNA damage response including repair, heterochromatin formation, and somatic cell reprogramming. Among these biological functions, transcriptional repression and activation are the most studied.

Acetylation of histones is thought to relax condensed heterochromatin as the negative charge of acetyl groups can repel the DNA phosphate backbone charges, thus reducing the histone binding affinity for DNA. This hypothesis was validated by the discovery of the histone acetyltransferase (HAT) activity of several transcriptional activator complexes. Thirdly, it neutralizes the positive charge on lysines. H4K16Ac also has roles in transcriptional activation and the maintenance of euchromatin. Additional acetylations include K31ac and K79ac.