There are at least two tail stories associated with big scientific discoveries. One is Darwin’s story about the tail loss during human evolution process. The other story is associated with discovery of benzene ring structure. In his creative dream Kekule saw the snake (the linear carbon chain) eating its own tail. Even better representation of benzene structure is the comic image of six monkeys holding each other hands and tails. Nowadays, the most popular scientific story in the field of epigenetics is the story of histones and their tails. This time instead of monkey or snake, an elephant is the animal whose characteristics allegorically represent epigenetics.
We all know how the histone octamer wrapped with DNA represents a nucleosome – the first unit of chromatin formation. Histones, which are basic due to numerous arginines and lysines, easily attract negatively charged DNA and in that way facilitate formation of nucleosome. The nature of two materials is important but not sufficient for such complex biological function like efficient packaging of DNA and regulation of gene expression. For that reason both the DNA and histones are decorated by numerous chemical groups.
Post-translational modifications (PTMs) of histones and histone variants themselves can cause alternation of net charge, changes histone dynamics and interaction with other chromatin proteins. The extreme complexity of interactions that can be achieved by histone modifications inspired Jenuwein and Allis to launch an idea of “histone or epigenetic code”. Core histones consist of a N- terminal tail, the globular portion and a C terminus. PMTs were discovered first on the N-terminal tail of core histones. However, the logical question was: Are only the tails decorated or are there more?”
Indeed there was much more to be discovered. Tan et al. (2011) identified 67 previously undescribed histone modifications. Their findings expanded number of known histone marks by about 70%. Not only did they find that core histones can be modified at places other than the N-terminal tail, but they also discovered two new chemical modifications: lysine crotonylation (Kcr) and tyrosine hydroxylation (Yoh). Together with discovery of lysine succinilatyon and malonylation (Xie et al. 2012), the total number of chemical groups that can be added to a histone rose to seventeen.
The most studied PMTs are covalent modifications like methylation, acetylation and phosphorylation; the other modifications are: propionylation, butyrylation, formylation, ubiquitylation, citrullination, sumoylation, ADP ribozylation, deamination, proline izomerization, O-GlcNAc modification, hydroxylation, crotonylation, malonylation and succinylation. These modifications are required for regulation of cellular processes such as transcription, replication, repair and genomic stability; mistakes in any of these functions could result in CNS defects, cancers and other pathologies. The majority of these modifications are reversible, and that characteristic makes them an ideal target for drug treatments.
Characterization of PMTs depends on available technologies. For example the above comprehensive characterization of histone modifications and role of Kcr described by Tan et al. (2011), was possible only by integrated, mass spectrometry-based proteomics approach combined with ChIP-sequencing. Other popular methods enable high-throughput screening of HDAC inhibitors and bisulfite conversion of DNA; all together allowing new therapies based on epigenetics. Scientists here at Promega also developed unique tools to study epigenetic modifications.
Jenuwein and Allis 2001. Translating the Histone Code. Science 293, 1074–80.
Tan et al. 2011. Identification of 67 Histone Marks and Histone Lysine Crotonylation as a New Type of Histone Modification. Cell 146, 1016–28.
Xie et al. 2012. Lysine Succinylation and Lysine Malonylation in Histones. Molecular & Cellular Proteomics 11, 100–7.