Epigenetics: Concept & Development

Epigenetics is a regulatory system that controls gene expression without affecting the makeup of the genes themselves. Regulation of gene transcription has emerged as a key biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.

This regulation is mediated by selective and reversible modifications of DNA and of proteins, especially histones, that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications are made by enzymes, many of which have specific genetic alterations that cause human disease. Reversible inhibition of the activity of disease-associated chromatin-modifying enzymes offers a clear mechanism for small molecule drugs as personalized therapeutics in diseases such as cancer, inflammatory diseases, metabolic diseases and neurodegenerative diseases.

The Histone Code Hypothesis

In 2001, Jenuwein and Allis proposed in their paper “Translating the histone code” (Science 10;293(5532):1074-80.) that the genome output is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Histones associate with DNA to form chromatin fibers, which in turn make up the more familiar chromosome.

The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure by silencing or activating entire regions of the chromosome and the genes located there.