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Epigenetics: A Turning Point in Our Understanding of Heredity

The views expressed are those of the author and are not necessarily those of Scientific American.


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A DNA molecule that is methylated on both strands on the center cytosine. Christoph Bock, Max Planck Institute for Informatics. Image used by permission of its author.

In a study published in late 2011 in Nature, Stanford University geneticist Anne Brunet and colleagues described a series of experiments that caused nematodes raised under the same environmental conditions to experience dramatically different lifespans. Some individuals were exceptionally long-lived, and their descendants, through three generations, also enjoyed long lives. Clearly, the longevity advantage was inherited. And yet, the worms, both short- and long-lived, were genetically identical.

This type of finding—an inherited difference that cannot be explained by variations in genes themselves—has become increasingly common, in part because scientists now know that genes are not the only authors of inheritance. There are ghostwriters, too. At first glance, these scribes seem quite ordinary—methyl, acetyl, and phosphoryl groups, clinging to proteins associated with DNA, or sometimes even to DNA itself, looking like freeloaders at best. Their form is far from the elegant tendrils of DNA that make up genes, and they are fleeting, in a sense, erasable, very unlike genes, which have been passed down through generations for millions of years. But they do lurk, and silently, they exert their power, modifying DNA and controlling genes, influencing the chaos of nucleic and amino acids. And it is for this reason that many scientists consider the discovery of these entities in the late 20th century as a turning point in our understanding of heredity, as possibly one of the greatest revolutions in modern biology—the rise of epigenetics.

Epigenetics and the state of chromatin

In Brunet’s lab, epigenetic inheritance is a big deal. Their Nature paper was the first to describe the phenomenon as it applies to longevity across generations, a breakthrough that emerged out of their quest to better understand the role of chromatin in inheritance.

Chromatin is a compact fiber of proteins and DNA that exists in either a condensed or a relaxed state. It assumes its condensed form during cell division in order to facilitate the splitting of chromosomes for distribution to daughter cells. Segments of the fiber, however, may retain this form when a cell is not dividing, with the result that genes occurring in these segments are fixed in an inactive state. Other stretches of the fiber, on the other hand, relax and open to allow regulatory proteins to access the DNA and activate genes.

Certain epigenetic modifications, such as the binding of methyl groups to histone proteins, the bobbins around which DNA is wound for chromatin packaging, are responsible for holding the fiber in an open state. But modifications are dynamic. During development, for example, chemical moieties attach to and detach from histones or DNA in an orchestrated fashion, their fluid dance aiding the execution of important functions, such as the establishment of patterns of gene expression for different types of tissues and the silencing of parental genes, a phenomenon known as parental, or genomic, imprinting.

Modifications can also accumulate during an organism’s lifetime. Because some of these acquisitions may affect DNA passed through the germline (in eggs and sperm) and may not be beneficial, they are erased at the time of reproduction, and the chromatin is returned to its original state. The process is not faithful, however, so some modifications slip through. In this way, chromatin modifications in parent DNA that are not reprogrammed are transmitted to the next generation.

Epigenetic inheritance of longevity in nematodes

The difference in coat color in these two genetically identical mice is due to epigenetic modifications. Jennifer Cropley, Victor Chang Cardiac Research Institute Image used by permission of its author.

There is increasing evidence that epigenetic modifications are transgenerational (inherited through multiple generations) in a variety of species. Examples include coat color in mammals, eye color in Drosophila, symmetry in flowers, and now longevity in C. elegans. These findings are exciting and raise intriguing questions about the seemingly limitless nature of epigenetics.

But the work of teasing out epigenetic modifications and their effects is arduous. To uncover the involvement of methylation in nematode longevity, Brunet and colleagues began by assessing the lifespans of C. elegans that were deficient in one of three genes, ash-2, wdr-5, or set-2; decreased or absent expression of these genes previously had been found to increase longevity in the species. They then crossed nematodes with genetic deficiencies with nematodes of normal genetic composition, pairings that in typical Mendelian fashion yielded wild-type (genetically normal) individuals, as well as individuals carrying the genetic alterations. Measurements of longevity were recorded for each of these populations and were compared with those of control populations (wild-type nematodes descended from wild-type parents). The findings revealed that the controls lived an average lifespan, whereas wild-type nematodes genetically identical to the control population but descended from mutant parents lived 20 to 30 percent longer.

Thus, the genetic deficiencies, though not inherited, had effected some type of change that endowed the genetically normal offspring of mutants with the same length lifespan that the mutants themselves experienced. The change, the Stanford team deduced, was methylation.

The proteins encoded by ash-2, wdr-5 and set-2 are part of a histone methylation complex known as H3K4me3, which is found across species ranging from yeast to humans. But the mechanisms underlying the inheritance of longevity are not clear. As Brunet explained, “We did not observe a global decrease in H3K4me3 levels in genetically wild-type descendants from mutants that are deficient in H3K4me3. We interpret that as saying there is not a global dearth of H3K4me3 that is inherited epigenetically.” Thus, the team’s current model is that when the proteins are scarce or absent, H3K4me3 methylation is lost at specific locations in the genome, and longevity-associated modifications in chromatin state, or possibly other types of modifications (e.g., non-coding RNAs), are passed to the next generation.

Transgenerational inheritance of acquired characters in humans

Epigenetics has given life to Lamarckism and the previously discarded idea that characteristics acquired during an individual’s life are heritable. In fact, many scientists already have warmed up to this idea. “There seems to be a renewed acceptance for the Lamarckian concept (in limited cases),” Brunet said. “This could change our understanding of inheritance in that it would add another component, probably minor, but present, in addition to Mendelian genetics.”

It also adds another layer of significance to our daily lives. A number of environmental factors, from nutrients to temperature to chemicals, are capable of altering gene expression, and those factors that manage to penetrate germline chromatin and escape reprogramming could, in theory, be passed on to our children and possibly our grandchildren.

But while several studies have suggested that transgenerational epigenetic inheritance can occur in humans, actual evidence for it is scant. Among the more convincing cases thus far involves the synthetic estrogen compound diethylstilbestrol (DES), which was used in the mid-20th century to prevent miscarriages in pregnant women. DES, however, dramatically increases the risk of birth defects. It is also associated with an increased risk for vaginal and breast cancers in daughters and an increased risk of ovarian cancer in maternal granddaughters of women exposed to DES during pregnancy. Studies in mice have suggested that neonatal DES exposure causes abnormalities in the methylation of genes involved in uterine development and uterine cancer; in mice these abnormalities were still present two generations down the line, suggesting a transgenerational effect.

Given the elusive nature of inherited epigenetic modifications, it seems that, despite decades of investigation, scientists remain on the brink of understanding. The possibilities, however, seem endless, even with the constraint that, to be inherited, epigenetic modifications must affect gene expression in the germline, a feat that even genetic mutations rarely accomplish. But with the skyrocketing prevalence of conditions such as obesity, diabetes, and autism, which have no clear genetic etiology in the majority of cases, as Brunet pointed out, “It seems that all complex processes are affected by epigenetics.”

While scientists continue to search for definitive evidence of transgenerational epigenetic inheritance in humans, the implications so far suggest that are our lifestyles and what we eat, drink, and breathe may directly affect the genetic health of our progeny.

Kara Rogers About the Author: Kara Rogers is a freelance science writer and the senior editor of biomedical sciences at Encyclopaedia Britannica, Inc. She is the author of Out of Nature: Why Drugs From Plants Matter to the Future of Humanity (University of Arizona Press, 2012), which explores the human relationship with nature and its relevance to plant-based natural products drug discovery and the loss of biodiversity. She holds a Ph.D. in Pharmacology/Toxicology and enjoys reading and writing about all things science. Follow her on Twitter at @karaerogers, and visit her website. Follow on Twitter @karaerogers.

The views expressed are those of the author and are not necessarily those of Scientific American.






Comments 7 Comments

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  1. 1. daedalus2u 4:05 pm 01/16/2012

    I wish that scientists would not use the term “Lamarckism” in relationship to epigenetics.
    Lamarckism is “the idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring.”

    http://en.wikipedia.org/wiki/Lamarckism

    Epigenetics is “heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence.”

    http://en.wikipedia.org/wiki/Epigenetics

    These are not the same thing. Lamarkism would require epigenetics and would be an example of epigenetics if it ever happened. There are no known examples of Lamarkism. Organisms don’t pass on acquired characteristics to their offspring.

    The examples on the wikipedia page on Lamarkism, that a high fat diet causes epigenetic changes that lead to offspring with an obese phenotype is not an example if an organism passing on acquired characteristics.

    This is an example of an organism experiencing a certain environment (a high fat diet), and then activating epigenetic mechanism(s) (germ cell DNA methylation of specific genes) so that offspring would be better adapted to that environment (better able to store calories as depot fat). Organisms that could epigenetically program their offspring had more surviving descendants, so organisms that can epigenetically program their offspring are common.

    The evolved process by which an organism’s physiology converts its present physiological state into epigenetic programming of germ cells, is not a process of “passing on acquired characteristics”. It is much more complicated than that.

    Link to this
  2. 2. RICHARDLLL 11:33 am 01/17/2012

    Epigenetics has already been shown to induce RNA editing (RNA Editing to Create ‘Acquired Characteristics’ Appears Common, Nature, May 19, 2011) and RNA is easily turned into DNA by reverse transcriptase (the human genome contains 300,000 genes for this enzyme, all currently considered ‘junk’)
    I think we should prepare ourselves for a “post-modern synthesis of Lamarckism and Epigenetics” as a replacement for the current “modern synthesis of Darwinism and Genetics.”

    Link to this
  3. 3. Black Eagle 12:00 pm 01/17/2012

    daedalus2u I would disagree, “Lamarckism” is an exactly appropriate term to use, and not just from examples out of epigenetics.

    Also a tip: Citing Wikipedia as a source does you no credit. Any student of mine who uses such untrustworthy sources gets a failing grade.

    Link to this
  4. 4. kp10krk 10:18 pm 01/17/2012

    How amazing is it that there is a mechanism to move information through or around the meiotic process and into offspring without altering the genotype? That the gene expression (or repression) may fade over generations and that some effects are sex-linked only broaden the puzzle. Damn I love science!

    Link to this
  5. 5. Torbjörn Larsson, OM 1:17 am 01/18/2012

    I don’t know many practicing biologists, but they all seem to agree that epigenetics is not “A Turning Point in Our Understanding of Heredity”:

    “I like to argue that what multigenerational epigenetic effects do is blur out or modulate the effects of genetic change over time, and it might mask out or highlight allelic variation, but ultimately, it’s all about the underlying genetic differences.”

    And:

    “So developmental genetics, and evo devo, are fascinating areas that produce a stream of surprising discoveries. But they’ve done nothing to alter the going paradigm of neo-Darwinian evolution. It is telling that, for example, Sean Carroll, a famous practitioner of “evo devo” and a popular writer, is a firm adherent to neo-Darwinism. What we learn from these areas is precisely how evolution has acted to sculpt bodies, but it still does so using randomly-generated genetic variation and good old natural selection (and yes, Larry Moran, genetic drift also plays a role).”

    “Why is this “revolutionary?” Because some of the inherited changes of genes appear to be “Lamarckian,” that is, they aren’t really changes in DNA sequence itself, but environmental modifications of DNA that can be passed from one generation to the next. And if such “nongenetic,” environmentally-acquired inheritance were common, that would be a revolution in the way we think about evolution.

    So what’s the evidence for this “revolutionary” notion? Forbes simply offers up the same tired old anecdotes I’ve addressed before: [...]

    Well, I won’t flog poor Mr. Forbes with the fact that these are only a few trivial examples of the phenomenon, examples that don’t appear to have any evolutionary importance. Nor will I flog him with the fact that when we can dissect the genetic basis of real adaptations in real organisms, they invariably turn out to rest on changes in DNA sequence, not in environmental and non-DNA-based modifications of nucleotides.”

    “So, Mr. Forbes, our “cherished dogma” of non-Lamarckian inheritance still holds strong, and you’ve done your readers a disservice by implying otherwise. Lamarckism is not a “heresy,” but simply a hypothesis that hasn’t held up, despite legions of evolution-revolutionaries who argue that it flushes neo-Darwinism down the toilet. If “epigenetics” in the second sense is so important in evolution, let us have a list of, say, a hundred adaptations of organisms that evolved in this Larmackian [sic] way as opposed to the old, boring, neo-Darwinian way involving inherited changes in DNA sequence.

    Forbes can’t produce such a list, because there’s not one. In fact, I can’t think of a single entry for that list.

    Science journalists — meh. They’re always trying to argue that Darwin was wrong and that evolution is about to undergo a Kuhnian revolutionary paradigm. But what they really want is readership, and you don’t get readers by writing that the conventional wisdom happens to be correct.”

    @ Black Eagle:

    Another tip: I think you mean primary data, not the context data that daedalus2u used. Note the several instances of Wikipedia use in my last link. Coyne is, to my knowledge, an evolutionary biologist of good standing that has passed (and passed out) many grades.

    _Not_ using available web resources is, well, not even aspiring to be non-Lamarckian.

    Link to this
  6. 6. daedalus2u 12:52 pm 01/18/2012

    Black Eagle, no.

    I was citing wikipedia for the definitions of the terms I quoted. For that, it is perfectly acceptable, and because I quoted them exactly (note the quotation marks) I needed to cite the source. No source is perfectly reliable. All sources need to be used only by those able to think critically and understand the underlying material, which you seem to not understand. Read the definitions I cited again, and try to understand how it is not “exactly appropriate” to say Lamarkism and epigenetics are the same.

    What is the mechanism by which organisms “decide” which DNA to epigenetically modify and how in germ cells so as to induce Lamarkism based on characteristics that somatic cells have acquired? (note I have put “decide” in quotation marks because I am using it metaphorically because individual germ cells don’t have cognition and so can’t decide anything). Because they can’t “decide”, any teleological argument that they can is wrong. It is bad form to use a term (Lamarkism) that posits a teleologic explanation.

    None of the germ cells that form the gametes that will form the next generation of offspring has participated in any of the acquired characteristics of the somatic cells of the organism. The germ cells that will form sperm cells are in the testis and remain there for the life of the organism. Metabolic stress on the liver, heart, kidneys, brain, occurs in liver cells, heart cells, kidney cells and brain cells respectively. How do the germ cells get “the message” to differentially epigenetically program DNA in gametes to produce a differential developmental program that results in a differential adult phenotype in offspring from those gametes?

    For example, the usually way that organisms develop a larger phenotype is though increased levels of growth hormones and androgens. Exercise will produce higher levels of growth hormones and androgens. Growth hormones and androgens are not produced by the tissues that grow bigger in response to exercise. So how is it that a larger phenotype produces larger offspring (or does it?)?

    The problem with considering epigenetics and Lamarkism to be “the same” is that it trivializes the (essentially completely unknown) extremely complicated mechanisms by which epigenetics specifically and differentially regulates DNA expression in offspring. There have to be physiological pathways by which parent phenotype affects DNA epigenetically programming in gametes. The limits of those pathways and what physiological parameters in the parent differentially affect DNA programming in the gametes will affect the range of what offspring characteristics can be affected and to what degree.

    The problem with the simplistic and wrong teleologic idea equating Lamarkism and epigenetics, is that when researchers go to try and understand the extremely complicated physiology behind how DNA is epigenetically programmed in gametes, the facile and teleologic explanation of “oh, it is Lamarkism, we don’t need to fund that research”, may prevent the necessary research from being funded. Not because it isn’t worth funding but because the false meme of “Lamarkism equals epigenetics” has corrupted the understanding of physiology.

    Oh, and it is just as much an “argument from authority fallacy”

    http://en.wikipedia.org/wiki/Argument_from_authority

    to reject an argument as accept it due to its source. But nice pedantic way to get your students to appreciate that no authority is completely reliable.

    Link to this
  7. 7. iain carstairs 6:00 am 04/11/2012

    Actually there is a form of Lamarckism which hasn’t been mentioned here, in that a separated group of laboratory animals which learn certain behaviours or skills seem to affect the behaviour of the species as a whole, while being completely separated geographically.

    This is pointed out by Rupert Sheldrake in The Science Delusion, along with all the laboratory research which supports this finding, as well as similar findings in other fields, such as manufacturing, culture growth and so on.

    These results are dismissed by the Wise Ones only on the basis that no visible mechanism is yet known to them, i.e., rejected for the same reasons epigenetics were seen as an impossibility not long ago!

    Link to this

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