Histone octamer

thumb|Basic units of [[chromatin structure]]

In molecular biology, a histone octamer is the eight-protein complex found at the center of a nucleosome core particle. It consists of two copies of each of the four core histone proteins (H2A, H2B, H3, and H4). The octamer assembles when a tetramer, containing two copies of H3 and two of H4, complexes with two H2A/H2B dimers. Each histone has both an N-terminal tail and a C-terminal histone-fold. Each of these key components interacts with DNA in its own way through a series of weak interactions, including hydrogen bonds and salt bridges. These interactions keep the DNA and the histone octamer loosely associated, and ultimately allow the two to re-position or to separate entirely.

History of research

Histone post-translational modifications were first identified and listed as having a potential regulatory role on the synthesis of RNA in 1964. Since then, over several decades, chromatin theory has evolved. Chromatin subunit models as well as the notion of the nucleosome were established in 1973 and 1974, respectively. Richmond and his research group has been able to elucidate the crystal structure of the histone octamer with DNA wrapped up around it at a resolution of 7 Å in 1984. The structure of the octameric core complex was revisited seven years later and a resolution of 3.1 Å was elucidated for its crystal at a high salt concentration. Though sequence similarity is low between the core histones, each of the four have a repeated element consisting of a helix-loop-helix called the histone fold motif. Furthermore, the details of protein-protein and protein-DNA interactions were fine-tuned by X-ray crystallography studies at 2.8 and 1.9 Å, respectively, in the 2000s.

The histone octamer in molecular detail

Core histones are four proteins called H2A, H2B, H3 and H4 and they are all found in equal parts in the cell. All four of the core histone amino acid sequences contain between 20 and 24% of lysine and arginine and the size or the protein ranges between 11400 and 15400 daltons, making them relatively small, yet highly positively charged proteins. The heterodimer formation is based on the interaction of hydrophobic amino acid residue interactions between the two proteins.

Each of the four core histones, in addition to their histone-fold domains, also contain flexible, unstructured extensions called histone "tails". Treatment of nucleosomes with protease trypsin indicates that after histone tails are removed, DNA is able to stay tightly bound to the nucleosome. In addition to compacting the DNA, the histone octamer plays a key role in the transcription of the DNA surrounding it. The histone octamer interacts with the DNA through both its core histone folds and N-terminal tails. The histone fold interacts chemically and physically with the DNA's minor groove. Studies have found that the histones interact more favorably with A:T enriched regions than G:C enriched regions in the minor grooves. The N-terminal tails do not interact with a specific region of DNA but rather stabilize and guide the DNA wrapped around the octamer. The interactions between the histone octamer and DNA, however, are not permanent. The two can be separated quite easily and often are during replication and transcription. Specific remodeling proteins are constantly altering the chromatin structure by breaking the bonds between the DNA and nucleosome.

Histone/DNA interactions

Histones are composed of mostly positively charged amino acid residues such as lysine and arginine. The positive charges allow them to closely associate with the negatively charged DNA through electrostatic interactions. Neutralizing the charges in the DNA allows it to become more tightly packed. As the DNA wraps around the histone octamer, it exposes its minor groove to the histone octamer at 14 distinct locations. At these sites, the two interact through a series of weak, non-covalent bonds. The main source of bonds comes from hydrogen bonds, both direct and water-mediated. Histones are positively charged molecules which allow a tighter bonding to the negatively charged DNA molecule. Reducing the positive charge of histone proteins reduces the strength of binding between the histone and DNA, making it more open to gene transcription (expression). The basic premise of the technique is to free up a region of DNA that the histone octamer would normally tightly bind. While the technique is not well defined, the most prominent hypothesis is that the sliding is done in an "inchworm" fashion. In this method, using ATP as an energy source, the translocase domain of the nucleosome-remodeling complex detaches a small region of DNA from the histone octamer. This "wave" of DNA, spontaneously breaking and remaking the hydrogen bonds as it goes, then propagates down the nucleosomal DNA until it reaches the last binding site with the histone octamer. Once the wave reaches the end of the histone octamer the excess that was once at the edge is extended into the region of linker DNA. In total, one round of this method moves the histone octamer several base pairs in a particular direction—away from the direction the "wave" propagated.

Clinical relevance

Numerous reports show a link between age-related diseases, birth defects, and several types of cancer with disruption of certain histone post translational modifications. Studies have identified that N- and C-terminal tails are main targets for acetylation, methylation, ubiquitination and phosphorylation. New evidence is pointing to several modifications within the histone core. Research is turning towards deciphering the role of these histone core modifications at the histone-DNA interface in the chromatin. p300 and cAMP response element-binding protein (CBP) possess histone acetyltransferase activity. p300 and CBP are the most promiscuous histone acetyltransferase enzymes acetylating all four core histones on multiple residues. Lysine 18 and Lysine 27 on H3 were the only histone acetylation sites reduced upon CBP and p300 depletion in mouse embryonic fibroblasts. Also, CBP and p300 knockout mice have an open neural tube defect and therefore die before birth. p300−/− embryos exhibit defective development of the heart. CBP+/− mice display growth retardation, craniofacial abnormalities, hematological malignancies, which are not observed in mice with p300+/−. Mutations of both p300 have been reported in human tumors such as colorectal, gastric, breast, ovarian, lung, and pancreatic carcinomas. Also, activation or localization of two histone acetyltransferases can be oncogenic.

References

External links

HistoneDB 2.0 - Database of histones and variants at NCBI