12.5: Epigenetics

Aristotle thought that an embryo emerged from an amorphous mass, a “less fully concocted seed with a nutritive soul and all bodily parts”. The much later development of the microscope led to more detailed (if inaccurate) descriptions of embryonic development. In 1677, no less a luminary than Anton von Leeuwenhoek, looking at a human sperm with his microscope, thought he saw a miniature human inside! The tiny human, or homunculus, became the epitome of preformation theory.

William Harvey, also in the 17 th century, described changes in morphology in the developing embryos of chickens (and other animals). Harvey coined the term epigenesis to counter the notion that any tiny adult structures in eggs or sperm simply grew bigger during embryonic gestation. Meanwhile, other experiments were leading embryologists to the conclusion that the physical and chemical environment of an embryo strongly affected development. Thus temperature, pH, and in the case of chicken eggs, position of incubation, affect embryonic development. In a series of very elegant experiments reported in 1924, Hans Speeman reported that cells associated with differentiation of one region of an embryo could be transplanted to a different part of the same embryo, or to another embryo entirely, where it would induce new tissue development. He won the 1935 Nobel Prize in Physiology and Medicine for his discovery of embryonic organizers that induced morphogenesis.

Other embryologists (including Conrad Waddington) demonstrated that cells killed by freezing or boiling still induced morphogenesis after being placed on an embryo. Thus, actual chemicals influence embryogenesis. The fact that differences in physical or chemical environment could affect embryonic development led many to conclude that environment played the dominant role and that genes played only a minor one in an organism’s ultimate phenotype. Unlike most of his fellow embryologists, Waddington believed in a more equitable role of genes and environment in determining phenotype. Adapting the term epigenesis, he coined the term epigenetics to describe the impact of environment on embryonic development (1942, The Epigenotype. Endeavour. 1: 18–20).

At the time, the concept of epigenetics led to a nature vs. nurture controversy. We now understand that differences in environmental influence can cause individuals with the same genes (genotype) to vary in appearance (phenotype). A modern version of thenature vs. nurture argument has more to do with complex traits, for example how much do genetics vs. environment influence intelligence, psychology and behavior. There is much to-do and little evidence to resolve these questions…, and likely too many factors affecting these traits to separate them experimentally.

These days, the field of epigenetics looks closely at protein interactions in eukaryotes affecting gene expression. These interactions change the structure NOT of genes (or DNA), but of the proteins (and other molecules) that affect how DNA and genes are used. As we have seen, the control of transcription involves transcription factors that recognize and bind to regulatory sequences in DNA such as enhancers or silencers. These proteinDNA interactions often require selective structural changes in the conformation of the chromatin surrounding genes. These changes can be profound and stable, and they are not easily undone.

An example of epigenetics is inheritance of chromatin protein alterations that accompany gene expression changes in development. Given an appropriate signal, say a hormone at the right time, a few cells respond with chromatin rearrangements and the expression of a new set of genes. The new pattern of gene expression defines a cell that has differentiated. Hundreds, even thousands of such changes accompany progress from fertilized egg to fully mature eukaryotic organism. Every one of these changes in a cell is passed on to future generations of cells by mitosis, accounting for different tissues and organs in the organism. Hence, the many different epigenomes representing our differentiated cells are heritable.

To sum up, epigenetics is the study of when and how undifferentiated cells (embryonic and later, adult stem cells) acquire their epigenetic characteristics and then pass on their epigenetic information to progeny cells. As we’ll see shortly, epigenetic inheritance is not limited to somatic cells, but can span generations! First, let’s look at this brief history of our changing understanding of evolution.

Jean-Baptiste Lamarck proposed (for instance) that when a giraffe’s neck got longer so that it could reach food higher up in trees, that character would be inherited by the next giraffe generation. According to Lamarck, evolution was purposeful, with the goal of improvement.

Later, Darwin published his ideas about evolution by natural selection, where nature selects from pre-existing traits in individuals (the raw material of evolution). The individual that just randomly happens to have a useful trait then has a survival (and reproductive) edge in an altered environment.

Later still, the rediscovery of Mendel’s genetic experiments, it became increasingly clear that it is an organism’s genes that are inherited, are passed down the generations, and are the basis of an organism’s traits. By the start of the 20th century, Lamarck’s notion of purposefully acquired characters was discarded.

Epigenetic inheritance implies an epigenetic blueprint in addition to our DNA blueprint. This means that, in addition to passing on the genes of a male and female parent, epigenomic characteristics (which genes are expressed and when) are also passed to the next generation. Waddington suspected as much early on, calling the phenomenon genetic assimilation, and once again created controversy! Does genetic assimilation make Lamarck right after all? Prominent developmental biologists accused Waddington of promoting purposeful evolution. Waddington and others denied the accusation, trying to explain how epigenetic information might be heritable, without leading to purposeful evolution.

Is there in fact, an epigenetic code? Data from the small Swedish town of Överkalix led to renewed interest in epigenetic phenomena. Consider the meticulous harvest, birth, illness, death and other demographic and health records collected and analyzed by L. O. Bygren and colleagues at Sweden’s Karolinska Institute.

A sample of Bygren’s data is shown in the table below.

It looked to the good doctor as if environment was influencing inheritance! It is as if the environment was indeed causing an acquired change in the grandparent that is passed not to one, but through two generations… and in a sex-specific way!

230 Epigenetic Inheritance: First Inkling

This phenomenon was subsequently demonstrated experimentally with the exposure of pregnant rats to a toxin. Rat pups born to exposed mothers suffered a variety of illnesses. This might be expected if the toxic effects on the mother were visited on the developing pups, for example through the placenta. However, when the diseased male rat pups matured and mated with females, the pups in the new litter grew up suffering the same maladies as the male parent. This even though the pregnant females in this case were NOT exposed to the toxins. Because the original female was already pregnant when she was exposed, the germ line cells (eggs, sperm) of her litter had not suffered mutations in utero. This could only mean that epigenetic patterns of gene expression caused by the toxin in pup germ line cells (those destined to become sperm & eggs) in utero were retained during growth to sexual maturity, and then passed on to their progeny, even while gestating in a normal unexposed female.

For some interesting experimental findings on how diet influences epigenetic change in Drosophila click here. For recent evidence for a role of male DNA methylation in trans-generational epigenetic inheritance, check out this link.

These days, the term epigenetics describes heritable changes in chromatin modifications and gene expression. We now know that epigenetic configurations of chromatin that are most stable include patterns of histone modification (acetylation, phosphorylation, methylation…) or DNA (methylation, phosphorylation…). Such changes can convert the 30nm fiber to the 10nm ‘beads-on-a-string’ nucleosome necklace… and vice versa. Such changes in chromatin (chromatin remodeling) lead to altered patterns of gene expression, whether during normal development or when deranged by environmental factors (abundance or limits on nutrition, toxins/poisons or other life-style choices). The active study of DNA methylation patterns even has its own name, methylomics! Check out Epigenetics Definitions and Nomenclature for more epigenetic nomenclature.
Let’s close this chapter with a question and some observations. Can you be sure that your smoking habit will not affect the health of your children or grandchildren? What about your eating habits? Drinking? It is not a little scary to know that I have a gullible germline epigenome that can be influenced by my behavior, good and bad. And that my children (and maybe grandchildren) will inherit my epigenetic legacy long before they get my house and my money. And that may not be all… epigenetic memory in C. elegans can stretch to 14 generations! Read about epigenetic inheritance resulting from Dad’s cocaine use at Sins of the Father and about multigenerational epigenetic inheritance at Epigenetic Memory in Caenorhabditis elegans.

231 Experimental Demonstration of Germ-Line Epigenetic Inheritance