Have researchers discovered how epigenetic information is passed down during cell division?

Have researchers discovered how epigenetic information is passed down during cell division?

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For example, how are histone code patterns passed down?

This question was asked a few years ago in this thread:

How are epigenetic marks transmitted during cell division?

However, it has been a few years now, and I'd like to know if researchers have made any progress.

Clarification: I'm specifically interested in figuring out how chromatin modifications are epigenetically inherited. There seems to be some evidence that it can be inherited, but there doesn't seem to be a full explanation as to how.

A good source for what I'm talking about is a article published in 2010 called: "Epigenetics and the Origins of Paternal Effects", which goes into detail on experiments done on rats that show epigenetic traits being inherited across offspring. However, the article ended on a note saying that the evidence is speculative, and further research needs to be done. Here's the link:

How do cells divide?

There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells.

Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by certain genes. When mitosis is not regulated correctly, health problems such as cancer can result.

The other type of cell division, meiosis, ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of gene shuffling while the cells are dividing.

Revising Life’s Instructions?

Antony Jose, associate professor of cell biology and molecular genetics, argues that the instructions used to build and maintain a living organism are stored in the molecules that regulate a cell’s DNA and other functioning systems.
(Image by iStock)

Is DNA life’s recipe—or just a cupboard full of ingredients?

The standard view of heredity is that all information passed down from one generation to the next is stored in the genome. But Antony Jose, associate professor of cell biology and molecular genetics, argues in two new papers that the true story of the set of instructions used to build and maintain a living organism is much more complicated.

Jose presented his new theoretical framework for heredity—that these instructions are stored in the molecules that regulate a cell’s DNA and other functioning systems—in peer-reviewed papers published last week in the Journal of the Royal Society Interface and the journal BioEssays.

Jose’s theory, developed through 20 years of research on genetics and epigenetics, suggests scientists may be overlooking important avenues for studying and treating hereditary diseases, and current beliefs about evolution may be overly focused on the role of the genome, which contains all of an organism’s DNA.

“DNA cannot be seen as the ‘blueprint’ for life,” Jose said. “It is at best an overlapping and potentially scrambled list of ingredients that is used differently by different cells at different times.”

For example, the gene for eye color exists in every cell of the body, but the process that produces the protein for eye color only occurs during a specific stage of development and only in the cells that constitute the colored portion of the eyes. That information is not stored in the DNA.

In addition, scientists are unable to determine the complex shape of an organ such as an eye, or that a creature will have eyes at all, by reading its DNA. These fundamental aspects of anatomy are dictated by something else.

Jose argues that these aspects of development, which enable a fertilized egg to grow from a single cell into a complex organism, must be seen as an integral part of heredity. Jose’s new framework recasts heredity as a complex, networked information system in which all the regulatory molecules that help the cell to function can constitute a store of hereditary information.

Jose’s approach could help answer many questions not addressed by the current genome-centric view of biology, said Michael Levin, a professor of biology and director of the Tufts Center for Regenerative and Developmental Biology and the Allen Discovery Center at Tufts University

“Understanding the transmission, storage and encoding of biological information is a critical goal, not only for basic science but also for transformative advances in regenerative medicine,” said Levin, who was not involved with either published paper. “Antony Jose masterfully applies a computer science approach to provide an overview and a quantitative analysis of possible molecular dynamics that could serve as a medium for heritable information.”

Jose proposes that instructions not coded in the DNA are contained in the arrangement of the molecules within cells and their interactions with one another. This arrangement of molecules is preserved and passed down from one generation to the next.

In his papers, Jose’s framework recasts inheritance as the combined effects of three components: entities, sensors and properties, that together enable a living organism to sense or “know” things about itself and its environment. Some of this knowledge is used along with the genome in every generation to build an organism.

The folly of maintaining a genome-centric view of heredity, according to Jose, is that scientists may be missing opportunities to combat heritable diseases and to understand the secrets of evolution. In medicine, for instance, research into why hereditary diseases affect individuals differently focuses on genetic differences and on chemical or physical differences in entities.

But this new framework suggests researchers should be looking for non-genetic differences in the cells of individuals with hereditary diseases, such as the arrangement of molecules and their interactions. Scientists don’t currently have methods to measure some of these things, so this work points to potentially important new avenues for research.

“Given how two people who contract the same disease do not necessarily show the same symptoms, we really need to understand all the places where two people can be different—not just their genomes,” Jose said.

Inherit behaviors

For this to be possible, a pathway must first be opened for the transfer of RNA from neurons to germ cells, something that, according to the dogma, does not exist. But this is precisely what a team of researchers at the University of Maryland did in 2015 when they discovered that in the worm Caenorhabditis elegans certain strands of RNA produced in neurons can travel to germ cells and silence genes in the offspring, even up to 25 generations later.

In the worm Caenorhabditis elegans certain strands of RNA produced in neurons can travel to germ cells and silence genes in the offspring. Credit: HoPo

In June 2019, a study published by scientists at Tel Aviv University (Israel) extended these results, demonstrating that RNA produced in worm neurons affects their offspring’s foraging behaviour through germ cell transmission, and that this learning is transferred over several generations. According to the study’s director, Oded Rechavi, “these findings go against one of the most basic dogmas in modern biology.”

The following month, a study conducted by Giovanni Bosco of the Geisel School of Medicine at Dartmouth (USA) showed that Drosophila melanogaster fruit flies can inherit from their parents egg-laying behaviour induced in parents by contact with wasps that parasitize their larvae their descendants adopt the same behaviour without having experienced the threat themselves.

However, it should be stressed that what is observed in worms or flies does not necessarily apply to humans. But it could. As early as 2013, a study by Emory University showed that the fear induced in mice of a particular smell can also be transmitted to their offspring by epigenetic mechanisms. And a mouse is already much more like us.

“Does this happen in animals other than fruit flies and worms?” asks Bosco. “Yes, I am convinced that it does, and we just need someone clever to think of the right experiment to do in order to actually test it, in humans for example,” he tells OpenMind. “A new avenue is now finally becoming accessible to experimentation in a manner where we can start to understand molecular mechanisms and specific molecules that allow animals to inherit particular types of behaviour and memory.”

Study suggests fear can be passed on through genes

A newborn mouse pup, seemingly innocent to the workings of the world, may actually harbor generations’ worth of information passed down by its ancestors.

In the experiment, researchers taught male mice to fear the smell of cherry blossoms by associating the scent with mild foot shocks. Two weeks later, they bred with females. The resulting pups were raised to adulthood having never been exposed to the smell.

Yet when the critters caught a whiff of it for the first time, they suddenly became anxious and fearful. They were even born with more cherry-blossom-detecting neurons in their noses and more brain space devoted to cherry-blossom-smelling.

The memory transmission extended out another generation when these male mice bred, and similar results were found.

Neuroscientists at Emory University found that genetic markers, thought to be wiped clean before birth, were used to transmit a single traumatic experience across generations, leaving behind traces in the behavior and anatomy of future pups.

The study, published online Sunday in the journal Nature Neuroscience, adds to a growing pile of evidence suggesting that characteristics outside of the strict genetic code may also be acquired from our parents through epigenetic inheritance. Epigenetics studies how molecules act as DNA markers that influence how the genome is read. We pick up these epigenetic markers during our lives and in various locations on our body as we develop and interact with our environment.

Through a process dubbed “reprogramming,” these epigenetic markers were thought to be erased in the earliest stages of development in mammals. But recent research — this study included — has shown that some of these markers may survive to the next generation.

“When I was in school, this was against Darwin — it was ridiculed,” said University of Pennsylvania neuroscientist Christopher Pierce, who was not involved in the study but previously discovered an epigenetic inheritance related to cocaine. Male rats whose fathers were exposed to cocaine chose to ingest less of the drug than those rats whose fathers never took cocaine.

Pierce says he believes this is an adaptive effect — because cocaine is a toxin, the fathers passed down information to their pups that would help them survive and avoid the substance.

In the past decade, the once-controversial field of epigenetics has blossomed. But proving epigenetic inheritance can be a daunting, needle-in-a-haystack undertaking. Researchers need to measure changes in offspring behavior and neuroanatomy, as well as tease out epigenetic markers within the father’s sperm.

The DNA itself doesn’t change, but how the sequence is read can vary wildly depending on which parts are accessible. Even though all the cells in our bodies share the same DNA, these markers can silence all the irrelevant genes so that a skin cell can be a skin cell, and not a brain cell or a liver cell.

“This fine-tuning of gene expression occurs by epigenetics,” said postdoctoral researcher and study author Brian Dias of Emory’s Yerkes National Primate Research Center.

For instance, methyl molecules can bind to the sequence and block access to genes. Other proteins called histones act like spools for the 2 meters of DNA, about 6.5 feet, crammed into every tiny nucleus in our bodies. Some areas are so tightly wound up that those parts unreadable.

Dias combined his interest in animal development with neurobiologist Kerry Ressler’s focus on the mechanisms of fear learning. They taught two groups of male mice to fear odors by zapping their feet with an electric shock every time they blew scented air into their cages. The experimental group became afraid of cherry blossoms with a hint of almond, and the control group feared alcohol.

After three days of fear conditioning, the cherry blossom mice later reproduced. The resulting offspring, having grown to adulthood, had a heightened jumpiness to the cherry blossom smell, despite never having been exposed to it. They had no overreaction to alcohol.

They could also pick up on lesser amounts of cherry blossom in the air, which reflected their changes in olfactory and brain anatomy. When Dias stained only the cherry-blossom-detecting olfactory neurons blue, he saw significantly more of them coding for that smell as compared with the control mice.

The researchers also artificially inseminated females using the sperm from the original fear-conditioned mice, to attempt to get rid of any possible socially transmitted effects between the fathers and the females. The results were the same, suggesting epigenetic inheritance rather than environment.

The findings were also verified by comparing the epigenetic markers on the DNA of sperm, specifically on the gene responsible for detecting cherry blossoms. On the sperm of the cherry-blossom-fearing mice, there was less of the methylation that can silence genes, possibly pointing to a mechanism of how the information got passed down.

Pierce was impressed by the thoroughness of Dias’s and Ressler’s study.

“It’s a compelling finding,” he said. “The fact that epigenetic changes happen in mammals is just amazing.”

Does this mean we as humans have also inherited generations of fears and experiences? Quite possibly, say scientists. Studies on humans suggest that children and grandchildren may have felt the epigenetic impact of such traumatic events such as famine, the Holocaust and the Sept. 11, 2001, terrorist attacks.

“Those are really powerful studies — unfortunately so, since the effects have been detrimental to subsequent generations,” Dias said. But because environmental factors for human subjects can’t be controlled, it is difficult to parse out the effects of epigenetics alone.

There are some who are skeptical of even mammal studies of epigenetics, and Dias believes they are rightly so since the field of epigenetics is still relatively new.

What you should know about Epigenetics?

Epigenetics refers to the study of heritable modification of gene expression without involving changes to the DNA sequence (modification in phenotype but not a change in genotype) which affects how the information in genes is used and expressed by cells. This term came into use during the 1940s when Conrad Waddington, a British embryologist used it to define the interactions between gene products and genes, giving rise to observable characteristics in an organism.

A lot of studies have been conducted about this field which gave rise to a revolution of genetics and developmental biology. Scientists have been able to discover a wide range of chemical changes to DNA and histones that interact closely with the DNA in the nucleus. These changes assist in determining if or when a particular gene is expressed in an organism or cell.

Researchers understand how individual lifestyle and the environment influence epigenetic modifications. These changes can be expressed at various stages of a person’s life or even in future generations. Here is a perfect example:

Data epidemiology studies show that prenatal and postnatal environment issues can determine whether an adult will be vulnerable to behavioral problems and chronic diseases. Studies show that children born during the Dutch famine (1944 -1945) had high rates of obesity and coronary conditions as result of exposure to famine during early pregnancy unlike those not exposed to famine.

Epigenetics and Inheritance

Scientists have realized that some changes in epigenetics are passed on from parents to offspring. This phenomenon is commonly known as epigenetic inheritance. The mechanism through which the epigenetic data is inherited is not yet clear however, researchers know that this information is not contained in the DNA sequence. This can only mean that it is not passed on by the same process used for typical genetic information. Normal genetic information is encoded in the nucleotides that make up the DNA. This is the information passed down from generation to generation as long as the DNA replication mechanism is accurate.

Epigenetics and Biomedicine

Changes to epigenetics not only influence how genes are expressed in animals and plants, they also determine the differentiation of cells that have the potential to become many different cells. Basically, epigenetics modification enables cells that have the same DNA and are derived from one fertilized egg to become specialized as brain cells, liver cells and skin cells.

As processes of epigenetics become clearer, scientists have discovered that the chemical change at the level of genome also impact biomedical factors. This knowledge has made it possible for researchers to understand normal and abnormal biological mechanisms. It has opened the door to the possibility of preventing or ameliorating certain conditions.

Epigenetics and Cancer

Cancer is one of the human diseases closely associated with epigenetics. Studies conducted by Vogelstein and Feinberg in 1983 showed genes of colorectal cancer cells were more hypomethylated compared to normal tissues. These studies suggested that DNA hypomethylaton activate oncogenes and trigger instability in chromosomes while hypermethylation trigger mechanisms that inhibit tumor silencing genes.

Have researchers discovered how epigenetic information is passed down during cell division? - Biology

Common DNA modifications occur through methylation, a chemical process that can dramatically change gene expression, which regulates the eventual production of proteins that carry out the functions of an organism.

DNA encodes genetic information in its chemical bases: adenine, cytosine, guanine, and thymine. Methylated cytosine is the dominant DNA modification found in eukaryotes, a taxonomical classification that includes mammals, insects, worms, plants, and algae, but new papers have identified an adenine DNA methylation that also epigenetically regulates cellular function in green algae, worms, and flies.

Through epigenetics, organisms sometimes bypass the genetic code to transmit certain traits to their offspring. DNA modifications, without changing DNA sequence, carry out those transmissions.

Adenine DNA modification that epigenetically regulates cellular function in green algae discovered. Credit: Lei Chen

"The human genome is not static. It contains dynamic DNA modifications that carry key inheritable epigenetic information passed among generations of cells," said Chuan He, the John T. Wilson Distinguished Service Professor in Chemistry at University of Chicago and a Howard Hughes Medical Institute Investigator who group contributed to three Cell papers which report the presence and function of N6-methyladenine (6mA) in three organisms.

"The conservation of this modification from simple unicellular eukaryotes to vastly different worms and flies indicate its wide presence and functional roles," He said. "All three studies together uncover a potential new epigenetic mark on eukaryotic DNA. They open a new field of biology and chemical biology."

Worms and flies were not previously known to contain DNA methylations. The presence of 6mA in green algae (Chlamydomonas), has been known for more than 30 years, but "No one had any idea what it does inside green algae."

In one of the Cell papers, the team unveiled the function of 6mA in Chlamydomonas, a green algae of potential use in biofuel production.

"Genes that have methylated cytosine have been associated with reduced gene expression," said Mets, who counts Chlamydomonas among his research specialties. "What's different about adenine methylation is that it is associated with more strongly expressed genes. It's a missing piece in the puzzle of regulation at the DNA modification level, and that's an exciting thing."

Fearful Memories Passed Down to Mouse Descendants

Certain fears can be inherited through the generations, a provocative study of mice reports. The authors suggest that a similar phenomenon could influence anxiety and addiction in humans. But some researchers are sceptical of the findings because a biological mechanism that explains the phenomenon has not been identified.

According to convention, the genetic sequences contained in DNA are the only way to transmit biological information across generations. Random DNA mutations, when beneficial, enable organisms to adapt to changing conditions, but this process typically occurs slowly over many generations.

Yet some studies have hinted that environmental factors can influence biology more rapidly through 'epigenetic' modifications, which alter the expression of genes, but not their actual nucleotide sequence. For instance, children who were conceived during a harsh wartime famine in the Netherlands in the 1940s are at increased risk of diabetes, heart disease and other conditions &mdash possibly because of epigenetic alterations to genes involved in these diseases. Yet although epigenetic modifications are known to be important for processes such as development and the inactivation of one copy of the X-chromsome in females, their role in the inheritance of behaviour is still controversial.

Kerry Ressler, a neurobiologist and psychiatrist at Emory University in Atlanta, Georgia, and a co-author of the latest study, became interested in epigenetic inheritance after working with poor people living in inner cities, where cycles of drug addiction, neuropsychiatric illness and other problems often seem to recur in parents and their children. &ldquoThere are a lot of anecdotes to suggest that there&rsquos intergenerational transfer of risk, and that it&rsquos hard to break that cycle,&rdquo he says.

Heritable traits

Studying the biological basis for those effects in humans would be difficult. So Ressler and his colleague Brian Dias opted to study epigenetic inheritance in laboratory mice trained to fear the smell of acetophenone, a chemical the scent of which has been compared to those of cherries and almonds. He and Dias wafted the scent around a small chamber, while giving small electric shocks to male mice. The animals eventually learned to associate the scent with pain, shuddering in the presence of acetophenone even without a shock.

This reaction was passed on to their pups, Dias and Ressler report today in Nature Neuroscience1. Despite never having encountered acetophenone in their lives, the offspring exhibited increased sensitivity when introduced to its smell, shuddering more markedly in its presence compared with the descendants of mice that had been conditioned to be startled by a different smell or that had gone through no such conditioning. A third generation of mice &mdash the 'grandchildren' &mdash also inherited this reaction, as did mice conceived through in vitro fertilization with sperm from males sensitized to acetophenone. Similar experiments showed that the response can also be transmitted down from the mother.

These responses were paired with changes to the brain structures that process odours. The mice sensitized to acetophenone, as well as their descendants, had more neurons that produce a receptor protein known to detect the odour compared with control mice and their progeny. Structures that receive signals from the acetophenone-detecting neurons and send smell signals to other parts of the brain (such as those involved in processing fear) were also bigger.

The researchers propose that DNA methylation &mdash a reversible chemical modification to DNA that typically blocks transcription of a gene without altering its sequence &mdash explains the inherited effect. In the fearful mice, the acetophenone-sensing gene of sperm cells had fewer methylation marks, which could have led to greater expression of the odorant-receptor gene during development.

But how the association of smell with pain influences sperm remains a mystery. Ressler notes that sperm cells themselves express odorant receptor proteins, and that some odorants find their way into the bloodstream, offering a potential mechanism, as do small, blood-borne fragments of RNA known as microRNAs, that control gene expression.

Contentious findings

Predictably, the study has divided researchers. &ldquoThe overwhelming response has been 'Wow! But how the hell is it happening?'" says Dias. David Sweatt, a neurobiologist at the University of Alabama at Birmingham who was not involved in the work, calls it &ldquothe most rigorous and convincing set of studies published to date demonstrating acquired transgenerational epigenetic effects in a laboratory model".

However, Timothy Bestor, a molecular biologist at Columbia University in New York who studies epigenetic modifications, is incredulous. DNA methylation is unlikely to influence the production of the protein that detects acetophenone, he says. Most genes known to be controlled by methylation have these modifications in a region called the promoter, which precedes the gene in the DNA sequence. But the acetophenone-detecting gene does not contain nucleotides in this region that can be methylated, Bestor says. "The claims they make are so extreme they kind of violate the principle that extraordinary claims require extraordinary proof,&rdquo he adds.

Tracy Bale, a neuroscientist at the University of Pennsylvania in Philadelphia, says that researchers need to &ldquodetermine the piece that links Dad's experience with specific signals capable of producing changes in epigenetic marks in the germ cell, and how these are maintained&rdquo.

&ldquoIt's pretty unnerving to think that our germ cells could be so plastic and dynamic in response to changes in the environment,&rdquo she says.

Humans inherit epigenetic alterations that influence behaviour, too, Ressler suspects. A parent&rsquos anxiety, he speculates, could influence later generations through epigenetic modifications to receptors for stress hormones. But Ressler and Dias are not sure how to prove the case, and they plan to focus on lab animals for the time being.

The researchers now want to determine for how many generations the sensitivity to acetophenone lasts, and whether that response can be eliminated. Scepticism that the inheritance mechanism is real will likely persist, Ressler says, &ldquountil someone can really explain it in a molecular way&rdquo, says Ressler. &ldquoUnfortunately, it&rsquos probably going to be complicated and it&rsquos probably going to take a while.&rdquo

This article is reprinted with permission from Nature magazine. It was first published on December 1, 2013.


As can be seen from the previous section, epigenetics and the evolution of plants is inextricable. Yet despite this now obvious statement, epigenetics is seldom discussed in a context of taxonomy and systematics, or population biology and conservation. Only one recent review, by Kalisz and Purugganan (2004), has considered the importance of epialleles in population genetics and evolution. Here, an attempt is made to redress the balance.

Taxonomy and systematics

The first encounter between epigenetics and systematics occurred at the birth of modern systematics when Linnaeus became aware of the ‘monstrous’ peloric variant of Linaria vulgaris, now known to be caused by hypermethylation of Lcyc. So different in basic floral morphology was this spontaneous variant, illustrated in Fig. 4, it caused Linnaeus considerable concern (for historical review, see Gustaffson, 1979). The fact that epigenetic variants can generate stable morphological changes in plants, to the point of homeotic transformations, cannot be ignored any longer by those studying plant systematics. As much taxonomy is still based on analysis of morphological features, it would seem that an obvious deduction is that some plant species may have been misclassified, and merely represent epigenetic variants of one species. This problem may be particularly acute in taxa where hybridization is frequent and from locations where sampling is patchy. Conversely, by virtue of the ease of reproductive isolation through ploidy change and, perhaps, through alterations in imprinted genes without associated ploidy changes, there may be more ‘cryptic’ species in plants, difficult or impossible to distinguish by morphology, than previously assumed.

Epigenetic control of floral symmetry in Linaria vulgaris (common toadflax). Right: wild-type L. vulgaris where the Lcycloidea locus controlling dorso-ventral patterning is expressed normally. Note the zygomorphic flower with the ventral petal lobe displaying a spur. Left: the peloric epimutant shows hypermethylation of the Lcyc sequence and loss of expression of Lcyc. The flowers show greater radial symmetry as the ventral petal lobe is repeated five times. The plant shown here is homozygous for the Lcyc epiallele heterozygotes show normal floral development.

Epigenetic control of floral symmetry in Linaria vulgaris (common toadflax). Right: wild-type L. vulgaris where the Lcycloidea locus controlling dorso-ventral patterning is expressed normally. Note the zygomorphic flower with the ventral petal lobe displaying a spur. Left: the peloric epimutant shows hypermethylation of the Lcyc sequence and loss of expression of Lcyc. The flowers show greater radial symmetry as the ventral petal lobe is repeated five times. The plant shown here is homozygous for the Lcyc epiallele heterozygotes show normal floral development.

Another consideration dictated by the epigenetic revolution relates to the evolution of plant characteristics. If, in a given taxonomic group, some genes controlling certain characteristics (e.g. stamen number, floral symmetry) are initially (or become) unusually labile at the epigenetic level, it would be expected that these characteristics would be more subject to repeated modification, loss or gain in the clade. In phylogenies of certain taxa, the frequent change or reversibility of some characteristics could be rooted in epigenetics. This idea will be illustrated by two different examples. A gene susceptible to stable silencing by hypermethylation of the promoter may become furtherentrenched in an inactive state by virtue of increased rate of mutation of the methyl-cytosine leading to functional change. Alternatively, when a gene is regulated by a miRNA, just a few nucleotide changes in the site of complementary binding to the miRNA could render the mRNA less susceptible or completely immune to regulation. Ectopic or over-expression by this mechanism could result in modification, loss or gain of a characteristic.

We have already hypothesized that rare saltatory changes in multiple characteristics could come about by virtue of aberrations in the epigenetic machinery. To reiterate, there is also supportive evidence that allopolyploid hybridization can lead to widespread epigenetic changes, altered gene expression and phenotypic changes, so allopolyploid speciation can be rapid and involve changes in multiple characteristics. More fascinating still is the (frustratingly incomplete) evidence for substantial differences in epigenetic systems in the gametophyte between different angiosperm taxa. Even if such a saltatory event occurs very infrequently in a phylogeny, its manifestation may create an interesting situation. Traditional morphology-based analysis may face considerable problems in resolving the taxonomy and phylogeny of a clade where an event of this kind has happened. The occurrence of such events may assist in the explanation of why phylogenies based on the DNA sequence sometimes show that morphological change is out of phase in relation to change to the DNA sequence. Epigenetics may illuminate and increase the complexity of the debate on molecules versus morphology in plant systematics.

Population genetics and conservation

Implicit in the discussion above is that epigenetic regulation and epigenetic variation has the capacity to generate phenotypic variation that may (or may not) have adaptive value. Unfortunately, measuring epigenetic variation in plant genomes is much more complex than determining variation in DNA sequences. For example, digestion of genomic DNA with isoschizomers can reveal DNA methylation patterns, whilst bisulfite sequencing can reveal in detail the methylation patterns of individual sequences. However, unlike the relatively static DNA sequence, methylation patterns can vary dramatically upon even the same DNA sequence, depending on factors such as environment and developmental stage, making sampling more complex. For instance, genomic DNA methylation levels have been shown to increase with developmental age, from seedling to mature plant, even in ephemeral species such as Arabidopsis thaliana ( Ruiz-García et al., 2005). This adds another new set of problems to generating data on DNA methylation patterns. At least there are some data for variation in populations of A. thaliana, with considerable variation between ecotypes in methylation detected at rRNA gene repeats ( Riddle and Richards, 2002). Detectable differences between ecotypes at the sequence level of the rRNA genes were negligible, though substantial differences in gene copy number were evident. QTL analysis of the control of this trait was performed by Riddle and Richards unsurprisingly, the major determinant of methylation mapped to the rRNA repeats themselves is probably due to the strong inheritance of parental epigenetic states at these loci. However, this could not account for all of the variation between ecotypes and trans-acting modifier loci affecting methylation whichwere shown to exist. These QTL loci contained strong candidates for genes controlling methylation such as KRYPTONITE and DNA methyltransferases. Of course, DNA methylation patterns are but one facet of epigenetic variation. The technology to assess variation in histones on a sequence-by-sequence basis and siRNA populations is in its infancy.

Measuring sequence variation by methods such as RAPD, RFLP, AFLP and VNTR amplification (for reviews, see Karp et al., 1996 Mueller and Wolfenbarger, 1999) will only give an estimate of variation in the DNA sequence. How much epigenetic variation is stored by the genomes of a population cannot be adequately described by present techniques, and a more detailed picture of the epigenetic variation in a model species, say Arabidopsis, would be a major step forward. How important is this otherwise ‘cryptic’ variation? Epigenetic data superimposed upon sequence data is likely to greatly improve the association of markers and traits, showing both continuous and discontinuous variation, in studies of populations. Another impact is that many repetitive sequences in genomes, previously considered neutral or nearly neutral, may emerge to show effects on traits and fitness. By affecting transcription of key genes, repetitive sequences and the chromatin they form may impact on quantitative variation and even effects on fitness. For example, some diseases in humans are now known to map to an increase in size of a repetitive DNA (reviewed in Sinden et al., 2002) and the structural effects generated by repeat expansion may block transcription of the gene ( Sakamoto et al., 1999, 2001). These effects may be local to exceptionally non-local. A superb example of the latter is paramutation at the B locus in maize, where the repetitive region, a tandem array, exhibiting the epigenetic changes that are governing paramutation behaviour is 100 kb upstream of the b1 coding region ( Stam et al., 2002). Even by smaller influences on factors such as chromatin structure that affect chromosomal architecture and recombination events, and the distance between enhancers and coding sequence, repetitive DNA can have a non-neutral and non-local effect on other sequences. With repetitive sequences emerging time and time again as a key target of epigenetic modification, selection must always be acting on repetitive sequences and it is quite wrong to dismiss these sequences as ‘junk’ evolving out of tempo with coding sequences.

What happens to epigenetic variation in populations affected by artificial pressures exerted by humans, more precisely in wild populations subjected to disruption by man and those in cultivation exposed to artificial selection (plant domestication and plant breeding)? Conservation biologists interested in conserving variation in plant populations should now heed the fact that epigenetic variation may be significant but cannot be readily measured. For example, in plant populations, epigenetics has been shown again and again to have a tremendous influence on plant fertility. In disrupted environments or through exposure to over-exploitation, small or fragmented wild populations may be subjected to in-breeding fixation of mutations in the epigenetic machinery that reduce fertility (amongst other effects) may have an impact on the long-term population genetics and even survival of the sub-populations. On the other hand, epigenetic variation induced in such backgrounds may have the opposite effect, allowing survival of the population in the face of abiotic and biotic adversity such as higher grazing pressure and climate change, by altering traits of selective value such as plant stature and flowering time. Metastable alleles at some loci may allow temporary escape of unfavourable conditions with considerable rapidity and without the permanence of nucleotide changes. Consequently, carrying or generating an ‘epimutational load’ may have advantages and disadvantages. On the other hand, epigenetic changes may assist in explaining why hybrids between native and non-native species may be unusually adaptable and become highly invasive. The invasive allopolyploid Spartina anglica, formed less than 150 years ago between a native and an introduced species, would be an interesting candidate for investigation. Surprisingly, genetic analysis of wild S. anglica clones showed no significant genetic changes compared with the parental species, even showing relative quiescence of transposable elements ( Baumel et al., 2001, 2002). Recently, significant epigenetic changes have been revealed using MSAP analysis ( Ainouche et al., 2003). In the invasive Senecio hybrids formed between S. squalidus (2n) and S. vulgaris (4n), the infertile S. baxteri (3n) and the derived fertile S. cambrensis (6n), there are significant changes to the transcriptome in the hybrids compared with the parental species ( Hegarty et al., 2005). Unfortunately, these have yet to be associated with epigenetic changes.

The pool of epigenetic variation, and the comparative ease with which it can be modified, may help to explain why some naturalized species can establish and become invasive in a short time, even though the naturalization process is accompanied by a massive bottleneck in genetic variation. An epigenetic perspective may also be useful in understanding how natural population bottlenecks in founder events can lead to formation of viable colonies and (eventually) speciation in isolated environments such as islands. In conservation biology, epigenetics may have much use, and questions such as whether epigenetic diversity is eroded in a similar way to genetic diversity in plant populations under pressure should be addressed in the future.

In plant domestication and plant breeding, population bottlenecks are also a feature, often together with hybridization and ploidy changes. A notable feature of artificial selection is that novel or extreme traits are frequently the object of selection, whether the effort is deliberate or unconscious. Are epigenetic variants selected for under these conditions? In clonally propagated plants, selection may particularly favour epigenetic variants as even non-heritable or metastable epigenetic states could be propagated indefinitely. Efforts are definitely needed to address this question, as it may help to explain why genetic diversity can drop dramatically yet phenotypic variation and phenotypic plasticity remains high. An outstanding example is analysis of AFLP variation in cultivated hybrids in Hemerocallis ( Tompkins et al., 2001). This genus is particularly useful as hybridization and selection from the handful of progenitor species, such as H. citrina and H. altissima, is only just over a century old but the original clones of the species remain in cultivation. As an intense level of selection has proceeded, producing cultivars increasingly novel and phenotypically divergent from the progenitor species, genetic diversity has decreased dramatically. This drop in genetic diversity is particularly sharp in tetraploids, a ploidy state derived artificially by plant breeders using colchicine and similar compounds. It would be interesting to determine whether epigenetic diversity in hybrid cultivars compared with progenitor species has decreased, remained stable or increased during this selection.

Wistar Study Demonstrates Heritability Of Non-Genomic Information

PHILADELPHIA (Sunday, October 31, 2004) - It's one of the defining tenets of modern biology: The characteristics of a living organism are coded into the organism's DNA, and only information in the DNA can be passed to the organism's offspring.

A new study by scientists at The Wistar Institute, however, suggests that this is not the full story. Instructions that control gene activity and are recorded solely in the molecular packaging of the DNA can also be passed to an organism's progeny, according to the new data. This heritable information is distinct from the genetic information coded in the DNA and is referred to by scientists as being "epigenetic" in nature. A report on the study appears in the November 1 issue of Genes & Development.

"The implication of our findings is that, parallel to the genetic information in our DNA, we also inherit epigenetic information to ensure that the regulation of our genes is executed correctly," says Jumin Zhou, Ph.D., an assistant professor in the gene expression and regulation program at Wistar and senior author on the new study.

In their experiments with fruit flies, Zhou and his colleagues investigated certain regulatory elements involved in controlling the homeotic gene complex, a large and complex gene region responsible for the proper development of the basic body plan. These vital genes have been highly conserved in evolution, appearing in species as divergent as fruit flies, mice, and humans. Large genes often employ highly sophisticated regulatory mechanisms: a mandatory promoter that activates transcription of the gene, enhancers that send instructions to the promoter, and specialized regulatory DNA elements such as insulators that can block or augment communication between enhancers and the promoter.

Zhou's team studied a regulatory element called the Promoter Targeting Sequence, or PTS. They showed that the PTS overcomes an insulator to facilitate, but also restrict, the activity of distant enhancers of a single promoter. Intriguingly, however, they also found that while the PTS required the insulator to target its designated promoter, the insulator could then be removed from the system without effect: With the PTS alone, no activity was seen. With the PTS and the insulator, the PTS effectively targeted its promoter. Then, with the insulator removed, PTS continued to target its promoter.

"The insulator was required to initiate a genetic process," Zhou says. "But then, even without the presence of the insulator, and even though no change was made to the gene, the process was self-perpetuating through multiple generations. This evidence points strongly to the fact of epigenetic inheritance."

The notion that epigenetic alterations can be passed from generation to generation complicates the standard model of genetics. Scientists have long held the view that acquired changes in the regulatory molecules associated with DNA are removed in the germ line cells, reset to a baseline state. Based on the current study, as well as other research conducted over the last few years, this does not appear to be entirely true.

These recent observations necessarily recall the theories of 19th Century scientist Jean-Baptiste Lamarck, who postulated that traits acquired by parents during their lives could be passed on to their offspring. Lamarck's ideas about evolutionary process were overtaken in subsequent years by those of naturalist Charles Darwin and, later, the monk Gregor Mendel. Recent advances in epigenetics, however, have begun to suggest that Lamarck may have been at least partly correct, for reasons and in ways that he could never have anticipated.

"I don&rsquot know of any example where an acquired trait has been written into the genome, into the DNA," says Zhou. "Still, it may be time to revisit the Lamarckian school of thought."

The lead author on the Genes & Development study is Qing Lin, Ph.D. Additional coauthors are Qi Chen, M.D., and Lan Lin, M.S. Assistant professor Jumin Zhou, Ph.D., is the senior author. All authors are based at The Wistar Institute. Funding for the research was provided by the National Institutes of Health, the March of Dimes Birth Defects Foundation, the Edward Mallinckrodt, Jr., Foundation, and the Concern Foundation.

The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center - one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.

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Materials provided by Wistar Institute. Note: Content may be edited for style and length.


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  3. Aragor

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