Epigenetics
Epigenetics refers to functionally relevant changes to the genome that do not involve changes in DNA sequence. Epigenetic switches occur in normal biological or disease processes or as a consequence of diet and other external environmental factors; and they induce changes in gene and protein expression. The form and function of every cell in the human body is determined by the genes and proteins it expresses and also by the signals it receives from the surrounding cells. Regulation of gene transcription and translation are therefore key biological determinants for cellular differentiation and function, and transcriptional imbalances play a significant role in a number of human diseases.
Every human cell contains about two meters of DNA organized into chromosomes. To allow for easy packing and unpacking, the DNA is wound around specialized proteins called histones to form nucleosomes. The nucleosomes in turn are organized into chromatin fibers that make up the chromosomes.
In 2001, Jenuwein and Allis proposed that modifications of the amino-terminal histone tails function as a "histone code", acting as a fundamental regulatory mechanism to control the conformational transition between transcriptionally active and inactive states of chromatin.
Modulation of the activity of disease-associated histone-modifying enzymes offers a clear path for the development of small molecule drugs to act as personalized therapeutics in diseases such as cancer, CNS, inflammatory and metabolic diseases.
Histone modifications are chemical changes of the amino acids of the amino-terminal tail introduced by specialized enzymes that alter chromatin structure by silencing or activating entire regions of the chromosome and the genes located there. Enzymes that add epigenetic marks are termed writers, enzymes that remove them erasers, and the enzymes that interpret them are readers of the histone code.
A number of histone modifications have been discovered including methylation, acetylation, ADP-ribosylation, ubiquitination, citrullination, and phosphorylation.
Many enzymes that modify or interpret histone modifications have been associated with human disease. Modulation of the activity of disease-associated histone-modifying enzymes offers a clear path for the development of small molecule drugs to act as personalized therapeutics in diseases such as cancer, CNS, inflammatory and metabolic diseases.