Histones and Histone Conservation
Histones are a family of nuclear proteins that compacts DNA in eukaryotic cells, and are, therefore, therefore structural components of chromosomes. Except for histone H1, histones are molecules with low molecular weight, comprised of 102-135 amino acids. Five subtypes of histones are known: H1, H2A, H2B, H3 and H4. The latter four histones (H2A, H2B, H3, H4) do form octamereric complexes containing two molecules of each histone, thus forming granule-like units known as nucleosomes, around which DNA segments of approximately 146 base pairs winds almost twice. In highly condensed chromosomes, nucleosomes all line up and are tightly held together by histone H1, the largest histone of the family. These repeated units of complexed histones (nucleosomes) and wrapped-around DNA segments constitute the chromatin fiber that can be compared to a pearl necklace.
The family of genes encoding histones are highly conserved, and are found in many different species. Most multicelular species present approximately 20 sets of copies of the five genes, because the amount of histones required to make new chromatin is roughly the same as the DNA mass. Histones are synthesized mainly in the beginning of phase S of the cell cycle, through increased transcriptional rates.
Genes located in DNA segments that are tightly wound around nucleosomes remain silent; i.e., are not able to transcribe the encoded nucleotide sequences to initiate protein synthesis. Histones in nucleosomes respond to two different kinds of gene expression regulations, methylation and acetylation. Methylation occurs by enzymatic-mediated mechanisms that add methyl groups to nucleosomes, hence inhibiting gene expression through the maintenance of chromatin condensation. In other words, genes adjacent to methylated nucleosomes remains in a non-transcriptional state. When methyl groups are taken away from a given group of nucleosomes, DNA strands partially unwind, allowing genes present to start transcription of the corresponding protein sequences they encode.
Evidence of the role of methylation in gene repression is the process of embryo development. In the first stages of embryo development, a very small number of genes are found methylated, whereas most genes actively express their products, i.e., proteins such as, enzymes, growth factors, etc. If methylation is experimentally induced, gene transcription is halted or slowed down. Another example is found during DNA synthesis. A newly transcribed DNA strand is not methylated; and methyl groups are only added after the new strand is paired with its complementary parental DNA strand.
Acetylation has an opposite effect on histones, inducing gene expression. Acetyl groups are also added to histones through enzymatic mechanisms involved in gene expression induction. For instance, during embryogenesis, high levels of acetyl groups are found binding to histones, thus allowing the active transcription of the necessary gene products to embryo development.
Histones in nucleosomes also respond to enzymatic-mediated addition and subtraction of acetyl groups. Acetylation of nucleosomes leads to expression of adjacent genes, whereas genes next to non-acetylated nucleosomes remain silent.
Both methylation and acetylation are known as epigenetic controls of gene expression. At present, a number of research works are investigating the implication of deregulated epigenetic controls in several birth defects and diseases such as: fragile X-chromosome syndrome, ICF (immune deficiency, centromere instability and facial abnormalities) syndrome, Rett syndrome, and leukaemia.
Histones and the nucleosomes they formed are found in DNA of different eukaryotic species, from yeast cells to mammals, through histone evolutionary conservation. Evolutionary conservation means that some biological features that were first developed by simple organisms like bacteria and unicellular prokaryotes, were further used by more complex life forms, such as sea urchins, fruitflies, plants, birds and mammals. Examples of conserved features are metabolic enzymes, hormones, cell cycle regulation systems, and structural proteins. Histones also show different degrees of evolutionary conservation among species. For instance, histones H3 and H4 show a high level of conservation, while H2A and H2B are moderately conserved. In other words, H3 and H4 are found in most eukaryotes, including the more primitive ones; and H2A and H2B in more recent and complex species.
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