Small steps toward understanding the epigenome

“You can think of it this way,” said Ren. “Neurons and skin cells share the identical set of genetic material – DNA – yet their structure and function are very different. The difference can be attributed to differences in their epigenome. This is analogous to computer hardware and software. You can load the same computer with distinct operating systems, such as Linux or Windows, or with different programs and the computer will run very different types of operations.

“Similarly, the unique epigenome in each cell directs the cell to interpret its genetic information differently in response to common environmental factors. Understanding the differences of epigenomic landscapes in different cell types, especially between pluripotent and lineage-committed cells, is essential for us to study human development and mechanisms of human diseases.”

[Source: EurekAlert]

This quote is from Professor Bing Ren, University of California San Diego, an author of a paper, Distinct Epigenomic Landscapes of Pluripotent and Lineage-Committed Human Cells published May 7 in Cell: StemCell. Not all geneticists would agree with what he said, or at least would disagree in emphasis. Professor Ren is making a case for the importance of epigenetics.

Epigenetics is a relatively new field of study that has a number of definitions. Here’s a good one:

“The development and maintenance of an organism is orchestrated by a set of chemical reactions that switch parts of the genome off and on at strategic times and locations. Epigenetics is the study of these reactions and the factors that influence them.”

[Source: University of Utah – Learn Genetics]

Epigenetics addresses questions like this: How is it that humans, with about 24,000 genes in their genome, are so much more complicated than the round worms, with 20,000 genes in their genome? Or the question addressed in the paper mentioned above: How much do the epigenomes of human embryonic stem cells differ from adult (lineage-committed) cells?

Epigenetics (‘epi’ meaning ‘over’ or ‘above’… genetics) understands that the principle mechanism of heredity is DNA and that the genome (the sequence of genes) provides the blueprint on which life is built. However, it also recognizes that DNA alone doesn’t really explain how human beings develop and become so much more complex than, say, the round worm, since the genetic code between the two isn’t all that different. The answer, according to the epigeneticist, is that the genome is surrounded (physically and figuratively) by an epigenetic landscape of amino acids, proteins, enzymes, RNA (in several forms), and probably non-coding portions of the genome itself (the introns) that interact with the genes of the DNA and also with the environment to guide the expression of genes.

Sometimes the epigenetic landscape is also called the epigenome, as if it were a counterpart to the genome. In a way it is. To use a crude analogy: If the genome is the blueprint, then the epigenome is the general contractor. The design of cells and the inherited characteristics of an organism are carried in the DNA. To a certain extent, the DNA also provides the design for the elements of the epigenome; but once the elements are in place, then the epigenome takes over the implementation of the DNA designs. It guides the chemistry of life (largely using RNA to guide the building of proteins) through the various stages of development, for example, from the original human embryonic stem cells as they go through the process of differentiating into the many kinds of adult body cells (blood, neuron, skin, etc.). Like a general contractor, the epigenome marshals resources, controls the rate of growth, determines what gets built where and when, and also acts as an intermediary between the blueprint of the DNA and the demands of the environment. Controlling immediate adaptation is a very important part of the epigenome.

Don’t get too carried away with an embodiment of an epigenome. Molecular biologists are really just beginning its exploration. They know it is organic chemistry – very complicated organic chemistry. They know that some of the epigenome comes not from the DNA in the nucleus but from the DNA of the mitochondria (inherited only from the female). They’re beginning to discover that large segments of the genome, the so called ‘junk DNA’, also contain information used by the epigenome to regulate the expression of genes. Yet this is obviously only the beginning.

Many epigenetic researchers, such as Professor Ren, are interested in how the epigenome guides the development of cells. To a certain extent it is the measure of how little is known about epigenetics that the question he addresses is: What’s the difference in the epigenetic landscape of the human embryonic stem cell, compared to the landscape of an adult (differentiated) cell? The answer, as it turns out, is – a lot.

For this particular study, the researchers looked at the structures that support DNA (kind of like scaffolding). These are called chromatin structures, and chromatin is built from specific proteins (histones). Histones are known for their adaptive properties; they are often affected by enzymes that are the principle tools of epigenetic processes. It is known that the chromatin structures interact with the genes and play a part in gene expression. For the study, chromatin structures in embryonic stem cells were compared with fibroblasts, the cell commonly found in animal connective tissue. It was found that nearly a third of the genome differs in chromatin structure between the two. Most of the changes were the result of dramatic repression of chromatin through the histone protein – a result of epigenetic influence.

Sometimes the steps toward scientific knowledge seem very small. On the other hand, when walking into unknown territory…

Small steps or not, the exploration of epigenetics has a kind of liberating feel to it. It seems like it’s the wide world of opportunity, change, and adaptation compared to the more narrow and limited commands of DNA genetics. It is also, of course, a hugely complicating factor. If we thought genetics was complicated (and it is), then the influence of epigenetics makes it more complicated probably by orders of magnitude. Of course, it took nature many millions of years to work out the complications – we ought to have the patience of a few decades to figure them out.

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