The genetic code contains only four letters. Organisms of staggering complexity are built from the detailed information contained in this four-letter alphabet. How this code is manifested requires many added layers of complexity and interaction with a host of variable systems.
Epigenetics describes modifications to chromosomal DNA that do not alter the genetic code, but persist through one or more cellular generations. Epigenetic modifications involve DNA methylation, the histone proteins structurally associated with DNA, and the density of packaging of discrete segments of DNA (nucleosomes). Epigenetic marking is a key element of both cellular differentiation and gene expression. Epigenetic marks participate in directing the development of pluri- and multipotent cells. These marks also participate in gene expression in fully differentiated adult cells, assisting in turning genes on and off during the cell’s lifetime of activity. Healthy cellular functioning depends on expression of certain genes and lack of expression (silencing) of others.
DNA methylation. This is the best understood type of epigenetic modification. The process involves adding a methyl group (CH3) to the nucleotide cytosine via a covalent bond. [Importantly, the source of these methyl groups is methionine, an essential amino acid found in meat, fish, eggs, yoghurt, and beans.] DNA methylation is primarily involved in gene silencing. For the most part, genes carrying these epigenetic marks are not transcribed and are therefore silent. But gene silencing may be inappropriate in certain circumstances and result in disease. For example, hypermethylation of cancer-suppressing genes will turn them off and allow cancerous cells to spread.
Histone proteins. When we view a cell’s chromosomes under the microscope we’re looking at discrete structures found in a resting cell. When a cell is active — absorbing things, making things, doing things, and excreting things — chromosomes lose their columnar structure and spread out into a lacy, weblike net of fibrils called chromatin. Whether in the form of chromatin or chromosomes, DNA is packaged together with histones which give specific 3-dimensional characteristics to the DNA strands.
The amino acid tails of histone proteins may be modified covalently to provide a range of epigenetic marks. Histone tails may undergo methylation, phosphorylation, or acetylation, each of which modifies the expression characteristics of the related gene. A histone code has been proposed which comprises a set of switches and combinations which help direct regulation of the higher-order genetic code. Histone modifications may work synergistically or antagonistically to further refine this regulatory sub-code.
Our understanding of these new concepts is continually being refined. Recent research suggests that some histone methylation marks may not correspond with gene silencing. And whereas histone acetylation is usually associated with gene activation, certain acetylation events may be related to gene repression.
As new information accumulates and new theories are developed in attempts to account for this new knowledge, it becomes clearer that “cracking the genetic code” was merely the first success. Identifying the four-letter code was a stunning breakthrough, and yet it was only the first step. Alice, going down her apocryphal rabbit hole, would appreciate the task confronting geneticists.
