12.9: 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 van Leeuwenhoek (who first saw and described pond-water protozoa and other animalcules), looked at a human sperm with his microscope and thought he saw a miniature human inside! The tiny human, or homunculus, became the epitome of preformation theory.

William Harvey, also in the \(17^{\rm th}\) century, described morphological changes in the developing embryos of chickens (and other animals). Harvey coined the term epigenesis to counter the notion that tiny adult structures in eggs or sperm simply grew bigger during embryonic gestation. Other experiments had led embryologists to conclude that the physical and chemical environment of an embryo strongly affected development. Thus temperature, pH, and in the case of chicken eggs, the position of incubation can affect embryonic development.

In a series of elegant experiments Hans Speeman reported in 1924 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 showed that cells killed by freezing or boiling still induced morphogenesis after being placed on an embryo. This clearly implicated a role for actual chemicals in 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, Conrad 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 the nature vs. nurture controversy. On the nature side, inheritance was mainly genetic, while the nurture side gave a dominant role to environmental chemistry. We now know that environmental differences can and do cause individuals with the same genes (genotype) to vary in appearance (phenotype). The modern version of the nature 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. Today, epigenetic (epi meaning ‘over’ or above) studies look at protein interactions in eukaryotes affecting gene expression, in other words at interactions superimposed on genes. These interactions change the structure NOT of genes or DNA, but of the proteins (and other molecules) that affect how and when genes are expressed. As we’ve seen, control of transcription involves transcription factors that recognize and bind to regulatory DNA sequences such as enhancers or silencers. These protein-DNA interactions often require selective structural changes in chromatin conformation around genes. These changes can be profound and stable, and they are not easily undone.

12.9.1. Epigenetic Inheritance in Somatic Cells

Examples of somatic cell epigenetics include the inheritance of chromatin protein alterations that accompany changes in gene expression that occur in development. Given the right signal, say a hormone at the right time, a few cells respond with chromatin rearrangements and new patterns of gene expression that can define a cell as differentiated. Hundreds, even thousands of changes to chromatin and gene expression accompany progress from fertilized egg to fully mature organism. Every one of these changes in a cell is passed on to future cell generations of cells by mitosis, accounting for the correct formation different tissues and organs in the organism. In this way, the many different epigenomes representing our differentiated cells are heritable. Somatic cell epigenetics is thus the study of when and how undifferentiated cells (embryonic and later, adult stem cells) acquire their differentiated characteristics and how they then pass on this information to progeny cells. As we’ll see shortly, epigenetic inheritance is not limited to somatic cells, but can span generations!

To help us understand this new aspect of inheritance and evolution, consider JeanBaptiste Lamarck’s belief that the ancestors of giraffes had short necks but evolved longer and longer necks because longer necks enabled them to reach food higher up in the trees. That new character would be inherited by the next giraffe generation. According to Lamarck, evolution was purposeful, with the goal of improvement. Later, Charles Darwin published his ideas about evolution by natural selection, where nature selects from preexisting traits in individuals (the raw material of evolution). The individual that just randomly happens to have a useful trait then has a survival (reproductive) edge in an altered environment. Evolution is thus not purposeful. Later still, with the rediscovery of Mendel’s genetic experiments, it became clear that it’s 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 twentieth century, Lamarck’s notion of purposefully acquired characters was discarded.

With this brief summary, let’s look at epigenetic inheritance across generations of sexually reproductive species.

12.9.2. Epigenetic Inheritance in the Germline

Epigenetic inheritance implies an epigenetic blueprint in addition to our DNA blueprint. This means that in addition to the passing on of genes from male and female parents, epigenomic characteristics (which genes are expressed and when) are also passed on from one generation to the next. Waddington suspected as much early on, calling the phenomenon genetic assimilation, and once again he created controversy! Does genetic assimilation make Lamarck right after all? Prominent developmental biologists accused Waddington of promoting Lamarck’s notions of purposeful evolution (the idea that what is best or necessary for the survival of an organism leads it to evolve a new gene for the purpose). Waddington and others denied the accusation, trying to explain how epigenetic information might be heritable, without leading to purposeful evolution. So, is there, in fact, an epigenetic code? Let’s look at data from the small Swedish town of Överkalix that 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 illustrated below in Figure 12.24.

Figure 12.24: Summary of health, birth, death, and demographic records for the town of Överkalix.

It looked to the good doctor as if environment were influencing germline inheritance, as if the environment were 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

CHALLENGE

Discuss the implications of the data in Figure 12.24 for the grandchildren of grandparents who grew up in hard times.

This phenomenon was subsequently demonstrated experimentally. For example, rat pups born to rats exposed to a toxin while pregnant, suffered a variety of illnesses. This might be expected if the toxic effects on the mother were visited on the developing pups (e.g., 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 was the case even though the pregnant females were not exposed to the toxins. Because the original female was already pregnant when she was exposed, the germline cells (eggs and sperm) of her litter had not suffered mutations in utero. This could only mean that the epigenetic patterns of gene expression caused by the toxin in pup germline cells (those destined to become sperm and eggs) in utero were retained during growth to sexual maturity, to be passed on to their progeny even while gestating in a normal, unexposed female.

231-2 Experimental Demonstration of Germ-Line Epigenetic Inheritance

For some interesting experimental findings on how diet influences epigenetic change in Drosophila, look at Diet and a Heritable Fly Epigenome. For an amusing (but accurate) take on epigenetics, check out the YouTube at Epigenetics Explained!. So, given the reality of epigenetic inheritance, let’s consider a most intriguing question: Is epigenetic inheritance (like Mendelian genetic inheritance) the result of natural selection?

Several studies have correlated adverse conditions during pregnancy in animals (including humans) with high incidences of health, behavioral and other anomalies in the adults. This was the case in Holland for children and grandchildren of mothers pregnant during the famine of the last winter of WWII, a season that became known as the Dutch Hunger Winter of 1944- 1945. As adults, these descendants had higher incidences heart disease, obesity, and diabetes. Such correlations were attributed to epigenetic changes in embryonic DNA in utero (read more at Dutch Grandkids After the Hunger Winter.

Here is the question that should occur to us: Why should so many survivors of life in an undernourished womb have suffered the same epigenetic changes at the same time? A study of methylation patterns in specific DNA regions in survivors of Dutch Hunger Winter pregnancies and a control group that missed the famine suggests an intriguing answer. The study found unique DNA methylation patterns in the surviving adults. To explain the survival of so many newborns that then suffered adult health anomalies, it was suggested that epigenetic modifications occur at random in embryos…, and then that some of these (i.e., the ones that marked the suffering adults) were selected during the pregnancy because they actually conferred a survival advantage to embryos (see a more complete discussion at Natural Selection in utero).

Did the many cases of epigenetic inheritance by large cohorts of individuals result from survival advantages of epigenetic natural selection? In other words, could epigenetic inheritance be subject to natural selection in the same way as genetic inheritance…, with more complex results?

These days, the term epigenetics describes how heritable change in chromatin modification (chromatin remodeling) affects gene expression. We now know that epigenetic configurations of chromatin that are most stable include modifications such as acetylation, phosphorylation, methylation of histones and methylation and phosphorylation of DNA. Such changes can convert the 30nm fiber to the 10 nm ‘beads-on-a-string’ nucleosome necklace… and vice versa. Chromatin remodeling can also lead to altered patterns of gene expression, whether during normal development or when caused by environmental factors such as 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 Nomenclature for more epigenetic nomenclature. Let’s close this chapter with some socially, culturally, and personally relevant observations and questions.

If environmental causes of epigenetic change persist in a unique or isolated location or demographic, could the natural selection of epigenetic traits result in geographic or demographic differences in epigenetic characters just as it has done for genetic characters?

Can we trace an epigenetic ancestry in the same way as our genetic one? That seems to be the case from recent comparisons of methylation patterns of DNA between Mexican and Puerto Ricans of Hispanic origin. DNA regions known to be sensitive to diesel emissions or intrauterine exposure to tobacco (and even social stressors) were differentially methylated in the two groups. Read more about this at Heritable Effects of Environmental Exposure.

Now think about the epigenetic consequences of smog that Los Angelinos endured and of lead toxicity to folks drinking lead-laden water in Flint Michigan (especially in children) the epigenetic effects of which remain to be seen. As you can see, epigenetics remains a hot topic, with much more yet to be concerned about! If environmental causes of epigenetic change persist in a unique or isolated location or demographic, could the natural selection of epigenetic traits result in geographic or demographic differences in epigenetic characters, just as it has done for genetic characters? Can we trace an epigenetic ancestry in the same way as our genetic one? That seems to be the case in a recent comparison of DNA methylation patterns between Mexicans and Puerto Ricans of Hispanic origin. The study revealed that DNA regions known to be sensitive to diesel emissions or intra-uterine exposure to tobacco (and even social stressors) were differentially methylated in the two groups. See details of this study at Epigenetics of Culture and Ethnicity.

Finally, thinking about epigenetic selection of clearly harmful traits, can we start to see them as analogous to the genetic selection of, say, β-globin gene mutations for sickle cell anemia that confer a survival advantage in one context (the threat of malarial parasites in mosquitoes), but that are harmful in another?

Here’s a bottom line you cannot avoid! Can you be sure that your smoking habit will not affect the health of your children or grandchildren? What about eating habits? Drinking? It is not just 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 money. And even that may not be the limit; epigenetic memory in Caenorhabditis elegans can stretch to as many as 24 generations! (Epigenetic Memory in C. elegans) Also, read about epigenetic inheritance resulting from Dad’s cocaine use Sins of the Fathers.

CHALLENGE

Chemical modification of DNA and chromatin proteins explains active euchromatin vs mostly inactive heterochromatin. It now seems that subtle physicochemical forces also lie behind interactions of chromatin regions that pack 2 meters of DNA into a 6 \(\mu\)m nucleus (see The Physics of Chromatin Folding or Chromatin Dynamics for more). While chromatin folding affects gene expression, interactions of chromatin domains also correlates with recombinations to rearrange lymphocyte gene segments that create antibodies of the immune response (Rearranging Immunoglobulin Genes). Since unwanted chromatin remodeling may cause disease, it must be stable as well as responsive to cell status. In what circumstances could chromatin folding result in epigenetic inheritance?