Epigenetics
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- Epigenetics - the study of stable alterations in gene expression that arise during development and cell proliferation
- Epigenetic phenomena do NOT change the actual, primary genetic sequence
- Epigenetic phenomena are important because, together with promotor sequences and transcription factors, they modulate when and at what level genes are expressed
- The protein context of a cell can be understood as an epigenetic phenomena.
- Examples include: DNA methylation, histone hypo-acetylation, chromatin modifications, X-inactivation, and imprinting.
One of the most fundamental questions in biology is: how does functional diversity arise from genetic homogeneity? Multicellular organisms present an apparent paradox: every cell in our body arises from a single-celled oocyte – the single, homogenous genetic precursor – but our bodies are composed of a myriad of radically and subtlely different cells. If the differences between these cells do not arise from their genetic heritage, from whence does this diversity arise? Enter epigenetics and the protein context of the cell.
Epigenetics is the study of stable alterations in gene expression that arise during development and cell proliferation. Epigenetic processes do not change the information contained within the genetic material itself, the ACTGs, but modulate gene expression through modification of meta-genetic information. However, epigenetic changes can be stable and passed on through mitotic cell divisions.
Remember – most living organisms share an enormous amount of genetic coding information; the basic building blocks (proteins) of life are very similar, if not the same, across widely divergent species; what separates the men from the amoebas is gene regulation, when and how a gene is expressed. Think of proteins as legos, and genetic regulation as the instructions on what to do with the legos. What separates the non-descript amalgamation of random blocks from the fantastic, futuristic, and imagination-inspiring space station complete with little space men and docking bay? The difference is reading the instructions on how to build what came with the box of legos. Regulation.
A large amount of the regulatory genetic instructions are written in the genetic code itself – for example, the 5’ regulatory promoters and the enhancer sequences. However, there is, necessarily, a rich external source of regulation, because, as mentioned earlier, every cell inherits essentially the same genetic material, and yet thousands of different cell-types eventually develop. DNA methylation is the best-understood example of stable epigenetic phenomena.
DNA methylation turns off gene expression by establishing a silent chromatin state through the addition of a methyl-group to (predominately) the cytosine residue of a CpG dinucleotide. The addition of the methyl-group causes a physical change in the state of the chromatin that inhibits the expression of any genes in the methylated region. And, interestingly, this inhibitory chromatin state is passed on to daughter cells during cell division. Methylation patterns are specific and orchestrated during an organism’s development, and are essential to an organism’s vitality. For example, during embryonic development, the oocyte is demethlyated, then re-methylated during gastrulation; mutational loss of the enzymes that mediate this methylation process is fatal to the developing embryo; we cannot survive without methylation. Also, abnormal, post-gastrulation methylation has been implicated in various cancers and is seen in culture cell-lines. Further, DNA methylation is believed to be important in maintaining X-chromosome inactivation, which is a vital process that turns off one of the X-chromosomes in females and assures a proper balance of sex-linked gene transcripts.
Beyond methylation, other epigenetic factors are important in determining the phenotype of a given cell. For instance, the specific protein context of a cell plays an intrinsic role in the expression profile of the cell. Many genes require specific transcription factors for expression: if the transcription factor is present, the gene is expressed, if the factor is not present, the gene is not expressed. Transcription factors also work to determine the level of gene expression – it is not necessarily a binary, on / off, system. Also, when a cell divides, its cytoplasm divides, donating its own particular cellular/protein context to its daughter cells. Thus, like DNA methylation, each cell inherits a unique protein context that influences its own specific phenotype and functional profile.
The question is, then, ‘why do we, as bioinformaticists, care about all of this?’ The answer is, unfortunately, because ‘all of this’ is going to make our job much more difficult. Bioinformatics typically utilizes genetic material stripped of contextual information, i.e. raw, naked genomic sequence data. In genefinding, for example, we attempt to answer questions such as, “is this region an expressed gene?”, but generally we ask these questions unmindful of the grotesque generalization we are making.
Douglass Haffstadler, in his book, Godel Escher Bach, uses the analogy of a record player and a record to illustrate how information cannot be isolated from its interpretive context. In this analogy, it is erroneous to think of the record as containing all of the information necessary to decode the music locked inside the vinyl. Just as a lock and key compliment each other, the record and the record player work together - the player embodies the information necessary to contextualize the miniscule bumps in the vinyl into music. Neither is of any use without the other. Bioinformatics is faced with an exactly analogous situation: the genetic record cannot be isolated from the context of the cell (the record player)., without stripping the signal of a large part of the relevant information.
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This work is licensed by Andrew Hughes under a Creative Commons Attribution License (CC-BY 1.0).
Last edited by Andrew Hughes on Jul 29, 2003 4:58 pm GMT-5.