Tag Archives: epigenetics

Pap tests could one day tell women if they have breast or ovarian cancer

Experts have identified changes in a woman’s cervix that can help detect tumors elsewhere in the body. These tests involve scraping cells from the cervix to detect any abnormalities that could cause cervical cancer. But researchers from Innsbruck University and gynecological cancer research charity The Eve Appeal found the cells from this test can also give clues and alerts for other types of cancers. With development, they state that the method used could one day predict the risk of developing ovarian, breast, womb, and cervical cancers from a straightforward smear pap test.

They developed their system using a process known as DNA methylation — epigenetic modifications to DNA that don’t alter the genetic sequence but do determine whether a gene expresses or stifles its function: in this case, forming or preventing cancer in the body. These modifications leave ‘methylation markers or signatures’ on genomic regions that scientists can read to determine what has occurred within a person’s body throughout their lifetime. Akin to the rings of a tree, this method can provide chronological clues as to what has happened in our biological life.

Researchers created the test, dubbed WID (Women’s Risk Identification), to analyze markers left by cancerous activity in the DNA of cervical cells. By calculating a woman’s WID, they hope to identify those with a high risk of developing ovarian, breast, womb, or cervical cancers: providing an early-warning system for medical teams to increase treatment outcomes.

The team was able to spot these modifications because they matched DNA markers found in diseased cervical, breast, ovarian, and womb biopsy tissue (a highly invasive procedure) to those found in the easier to access cells of the cervix — whose similar biological structures undergo the same hormonal changes as the tissues these cancers flourish in.

Finding cancer through the cervix

The first study examined cervical cell samples collected from 242 women with ovarian cancer and 869 healthy controls. To develop the WID risk scale, the scientists measured 14,000 epigenetic changes to identify ovarian cancer’s unique DNA signature to spot the presence of the disease in epithelial tissue scraped from the cervix.

They then validated the signature in an additional cohort of 47 women who had ovarian cancer and 227 healthy subjects. Results identified 71% of women under 50 and roughly 55% of the volunteers older than 50 who had previously tested positive for the disease — giving the tests an overall specificity of 75%. A test’s specificity is its ability to correctly identify people without the disease.

Professor Martin Widschwendter of the University of Innsbruck and UCL, heading up the research, said the findings suggest their WID index is picking up cancer predisposition, adding that the results were similar to a study on women with cancer of the womb. He is adamant their test cannot predict ovarian, with more studies needed.

A possible screening method for an undetectable cancer 

In the second study, the same team analyzed epigenetic changes in cervical cell samples provided by 329 women with breast cancer against those from the same 869 healthy volunteers in the first study. Using the WID index, they were able to identify women with breast cancer based on a unique epigenetic signature. The group once again confirmed these markers in a smaller consort of 113 breast cancer patients and 225 women without this condition.

The researchers also used the patterns to predict whether patients had breast cancer-but they didn’t say exactly how accurate the tests were. Instead, they stressed that further trials are needed-with the hope that clinicians could use their WID as a regular test for women in the future-specifically for those under fifty years of age who do not have access to screening for this disease.

“This research is incredibly exciting,” said Liz O’Riordan, a breast cancer surgeon who was also diagnosed with this disease. “At the moment, there is no screening test for breast cancer in women under the age of 50. If this test can help pick up women with a high risk of developing breast, ovarian, cervical, and uterine cancer at a younger age, it could be a game-changer.”

The team adds that these findings are also crucial for ovarian cancer, whose symptoms can be as benign as a bloated abdomen. The biggest killer of women out of gynecological-based tumors, this disease is diagnosed late by clinicians in an alarming 3 out of four cases.

But for now, Widschwendter says, the findings suggest that the molecular signatures in cervical cells may detect the predisposition to other women-specific cancers rather than providing a solid prediction of the disease.

Because of the pandemic, women have stopped taking pap tests

A pap smear test detects abnormal cells on the cervix, which is the entrance to the uterus from the vagina. Removing these cells can prevent cervical cancer, which most commonly affects sexually-active women aged between 30 and 45. In most cases, the human papillomavirus causes this cancer after being acquired through unprotected sex or skin-to-skin contact. To summarise, the whole point of these tests is to detect women at risk of developing cancer and encourage them to carry further health check-ups, not to find those displaying cancer symptoms.

Around the world, the number of women taking smear tests has dropped substantially during the pandemic. In England, for instance, one of the countries with the highest testing rates, just 7 out of 10 eligible women got a cervical check-up — and conditions are expected to worsen due to a new policy brought in by the UK government at the start of 2022, which saw all eligible women in Wales have their wait times increased from three to five years in between tests. The government expects to roll out the policy in England this year after the pandemic caused the delay of its initial release. Experts insisted the move was safe, but campaigners hit back at the plans, arguing it would cause preventable deaths by delaying the detection of cancer or pre-cancerous issues.

In a statement to the Guardian, the UK’s Secretary for Patient Safety and Primary Care says it’s “great to see how this new research could help alert women who are at higher risk to help prevent breast, ovarian, womb, and cervical cancer before it starts.” Until this time, cancer screening remained vital and urged all women aged 25 and above to attend their appointments when invited. The secretary did not remark on the new government policy.

An ovarian cancer specialist urged caution in interpreting the data: They show a “moderate association” between the methylation signature and ovarian cancer, said Dr. Rebecca Stone, the Kelly Gynecologic Oncology Service director at Johns Hopkins Hospital. “They are not showing that it’s predictive or diagnostic,” Stone stressed. Clarifying that to see whether the cervical cell signature predicts cancer, a study would have to observe a large group of women over a long period.

Filling the gap in screening options for women

In contrast, Athena Lamnisos, CEO of the Eve Appeal, emphasizes the importance of a new screening tool:

“Creating a new screening tool for the four most prevalent cancers that affect women and people with gynae organs, particularly the ones which are currently most difficult to detect at an early stage, from a single test could be revolutionary.”

The Eve Appeal goes on that women could get separate risk scores for each of the four cancers in the future where medical teams could offer those with high scores more active monitoring, regular mammograms, risk-reducing surgery, or therapeutics.

Ultimately, it’s better to prevent than to treat, and this method could offer women worldwide access to proper screening services that could save lives through the application of early intervention and preventative medicine.

Humans live much longer than chimps due to a slower epigenetic ‘clock’

Breakthrough advances in medicine and better nutrition have dramatically improved the longevity of the average human over the past two centuries. But that’s not to say that some couldn’t go on to live a long life even before the advent of modern medicine. As long as they were spared by disease, wars, and other risks that can bring an untimely death, humans could live to see their 70s, 80s, and even reach 100 years old as far back as ancient Rome.

The longevity of humans is somewhat exceptional among primates. Chimpanzees, our closest living relatives, rarely make it past age 50, despite them sharing over 99% of our DNA. In a new study, researchers think they’ve found our secret: chemical changes along our genome that occurred around 7-8 million years ago when our ancestors branched away from the lineage of chimps.

Slower ticker

There are tens of thousands of genes in the human genome, but that doesn’t mean all of them are active. For instance, through the methylation of DNA across certain sites of the genetic sequence, genes are locked in the “off” position. These modifications, known as epigenetic changes (‘epi’ means ‘above’ in Greek), do not alter the DNA sequence itself but, rather, simply regulate the activity of genes.

DNA methylation involves attaching small molecules called methyl groups, each consisting of one carbon atom and three hydrogen atoms, to segments of DNA. When DNA gains or loses a methyl tag, such events mark time. In fact, the changes are so consistent that methylation can be used as an “aging clock”. Previously, scientists were able to estimate a person’s chronological age based on their gene activity within less than four years.

In a new study, researchers at Duke University and George Washington University have analyzed age-related epigenetic changes in chimpanzees. They analyzed over 850,000 methylation sites in blood from 83 chimpanzees aged 1 to 59.

Just like in humans, aging also leaves its epigenetic signature on the genomes of chimps, the authors of the study found. More than 65,000 DNA sites changed in a clock-like fashion across the primates’ lifespan, some gaining methylation and others losing it.

The DNA methylation pattern was so reliable that the researchers could tell a chimp’s age from their genomes with an error within 2.5 years — much more accurate than other methods, such as estimating an animal’s age by measuring the amount of wear on their molars.

When compared to the epigenetic aging clock of humans, the researchers found that a chimp’s clock ticked faster. The authors aren’t sure that these changes actively contribute to aging or merely track the aging process. However, they hope they might eventually learn more about how gene regulation could be involved in physical and cognitive decline that often accompanies aging.

The findings appeared in the Philosophical Transactions of the Royal Society B.

Researchers document first evidence of epigenetic inheritance via sperm

Caenorhabditis elegans. Credit: Wikipedia.

For the first time, researchers at the University of California Santa Cruz have shown that epigenetic marks — changes in gene expression that does not involve changes to the underlying DNA sequence — can be transmitted from parents to offspring. Namely, the transmission of epigenetic marks by Caenorhabditis elegans sperm.

Epigenetic changes do not alter the DNA sequences of genes — the actual blueprint for life — but rather involve chemical modifications such as methylation of DNA and covalent modification of histone proteins that package DNA in the chromosomes. Epigenetic changes are handled in part by specialized proteins called transcription factors, which bind to specific sequences in our DNA.

These modifications influence the way an organism functions by activating or deactivating the expressions of certain genes at different stages of a cell’s development. Previously, studies have shown that such epigenetic modifications might be transmitted from one generation to the next. For instance, the epigenetic changes caused by a person’s diet and environmental stressors (i.e. pollution) could potentially be passed on to offspring who would bear these gene expression alterations without actually having to go through the same experience.

One famous example of epigenetics in action involves the case of a group of women who lived through starvation during the 1944 Nazi blockade of food supplies in the Western Netherlands. The harsh winter and food embargo caused pregnant women to birth smaller babies than they should have under normal conditions.

However, even though these children grew up in relative prosperity after the war had ended, their babies were also unexpectedly small. Later, researchers at the Columbia University Medical Center in New York found that the genetic response to starvation is passed down at least three generations. Even the genetic changes caused by trauma can get passed on to offspring, as demonstrated by a study of Holocaust survivors.

Susan Strome and colleagues at UC Santa Cruz wanted to learn how transgenerational epigenetic inheritance works at the molecular level. Other studies have shown that 10% of histone packaging is retained in both human and mouse sperm. But when Strome’s team analyzed C. elegans sperm, they found that its genome fully retains histone packaging, making this worm the perfect animal model for this study.

“We decided to look at C. elegans because it is such a good model for asking epigenetic questions using powerful genetic approaches,” said Strome in a statement.

“Like zebrafish, worms represent an extreme form of histone retention by sperm, which makes them a great system to see if this packaging really matters,” she added.

The researchers focused their efforts on H3K27me3, an epigenetic mark of repressed gene expression in a wide range of organisms. When this mark was removed from sperm chromosomes, the majority of the worm’s offspring became sterile. Next, the researchers want to establish whether this mark is sufficient to guide normal germline development.

To find out, the team employed a nifty experiment in which the analyzed a mutant worm whose chromosomes from sperm and egg were separated in the first division after fertilization. In other words, one cell of the embryo inherited sperm chromosomes and the other cell inherited only egg chromosomes.

This segregation allowed the researchers to breed worms whose germ line inherited only sperm chromosomes, allowing them to tease out only sperm epigenetic marks. These worms turned out to be fertile and had normal gene expression patterns.

“These findings show that the DNA packaging in sperm is important, because offspring that did not inherit normal sperm epigenetic marks were sterile, and it is sufficient for normal germline development,” Strome said.

So, the study’s findings not only document the transmission of epigenetic memory via sperm but also show that epigenetic information delivered by sperm to the embryo is both necessary and sufficient to guide proper development of germ cells in offspring. The study, however, does not answer whether the experience of a father can affect the health of his descendants — that’s a question which Strome’s lab hopes to answer in another study in which they starve worms or treat them with alcohol before reproducing.

“The goal is to analyze how the chromatin packaging changes in the parent,” she said. “Whatever gets passed on to the offspring has to go through the germ cells. We want to know which cells experience the environmental factors, how they transmit that information to the germ cells, what changes in the germ cells, and how that impacts the offspring.”

Stressed Lady and Child.

Stress as a child may leave you unable to cope with stress and depression later on

Experiencing stress in early life could prime your brain with a lifelong susceptibility to stress and depression by altering gene expression in the brain’s reward pathways, a new study found.

Stressed Lady and Child.

Image credits Bhakti Iyata.

It’s the gift that keeps on giving — even though you’d rather it stop. We are, of course, talking about stress. A new study from the Icahn School of Medicine at Mount Sinai reports that early-life stress may hard-wire a susceptibility to stress, mood fluctuations and even depression in the brain.

The study focused at how epigenetics can alter our ability to cope with stress. Epigenetics is basically our body’s way of fine-tuning DNA — by employing various molecules to regulate where, when, and how much certain genes are activated/expressed, our bodies can prompt pretty significant changes to what a gene does without changing the data is encodes. Epigenetic changes are handled in part by specialized proteins called transcription factors. These bind to specific sequences in our DNA and either promote or inhibit the expression of a gene.

We knew from previous studies that epigenetics play an important part in the way our brains develop. We also knew that early life stress increases the risk of subsequent depression and other syndromes — but why this happens, or if epigenetics plays a part, remained unanswered questions.

“Our work identifies a molecular basis for stress during a sensitive developmental window that programs a mouse’s response to stress in adulthood,” says Catherine Peña, PhD, and lead investigator of the study.

“We discovered that disrupting maternal care of mice produces changes in levels of hundreds of genes in the VTA [ventral tegmental area] that primes this brain region to be in a depression-like state, even before we detect behavioral changes. Essentially, this brain region encodes a lifelong, latent susceptibility to depression that is revealed only after encountering additional stress.”

The team found that the transcription factor orthodenticle homeobox 2 (Otx2) acts as a sort of master regulator for these genetic changes. They showed how baby mice stressed in a sensitive period (between the 10th and 20th after birth) had suppressed Otx2 in their VTA. Its levels would recover by the time the rats reached adulthood, but that initial suppression period was enough to set epigenetic changes in motion which lasted well into adulthood. So stress in early life can disrupt the way a brain develops, at least as far as gene programming governed by Otx2 is concerned.

Sleeper stress

The full effect of these changes only becomes apparent as the adult mice experienced additional stress. While all mice behaved normally, to begin with, those who experienced stress early on were more likely to succumb to depression-associated behavior as adults after experiencing social stress.

Finally, the team developed a viral treatment to check whether Otx2 was indeed responsible for the changes. The viral vectors would either increase or decrease Otx2 levels in mice’s brains, and the team reports that a suppression of Otx2 in early life was “necessary and sufficient” for mice to show greater susceptibility to stress as adults. Not only does the protein alter our brains’ ability to deal with stress in the long run, but in the short term as well.

“We anticipated that we would only be able to ameliorate or mimic the effects of early life stress by changing Otx2 levels during the early sensitive period.” says Dr. Peña. “This was true for long-lasting effects on depression-like behavior, but somewhat to our surprise we could also change stress sensitivity for short amounts of time by manipulating Otx2 in adulthood.”

This is the first study to use genetic data to understand how early development alters the development of the VTA and show how crucial it is for our ability to cope with stress and manage our emotions throughout life. However, more research needs to be done to pinpoint exactly which age intervals are key here.

The full paper “Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2” has been published in the journal Science.

Research identifies the genes that make you go through puberty

In a collaborative effort by the Oregon Healthy and Science University and the University of Pittsburgh, researchers identified the genes whose role is to trigger the onset of puberty, and manipulate them to delay puberty in female rats. They hope that the discovery will help determine exactly why causes early-onset puberty in females.

Image via redorbit

Medical literature holds that puberty begins around ages 10-11 for girls and around age 12 for boys, with variations on this from person to person. Now, the paper the OHSU team published in the journal Nature Communications allows us insight into how the brain fits into this complex process, controlling the sexual development of the body.

The biggest player in the process seems to be a supergroup of around 800 genes known as the Zinc finger (ZNF) family that neuroscientist Dr. Alejandro Lomniczi and his colleagues have found to be responsible for regulating the timing of puberty in advanced nonhuman primates. Some of these genes, they explain, function within the neoendocrine brain and work as “neurological brakes,” preventing puberty-related genes from activating during childhood.

The ZNF supergroup holds the blueprints for proteins that inhibit gene expression, allowing them to inhibit the onset of puberty. Knowing this allows Dr. Lomniczi’s team to determine what environmental factors are involved in precocious or early onset puberty, which has been linked to a number of cancers and other health issues.

“Deepening our understanding of how the brain controls the initiation of puberty will allow us to understand why girls are initiating puberty at much earlier ages,” Dr. Lomniczi said Wednesday in a statement.

“This knowledge may help build a foundation for developing new avenues to treat precocious puberty. Our suspicion, is that chemical substances contained in man-made products and other environmental factors, such as nutrition, may accelerate reproductive development by epigenetically antagonizing gene repressors such as ZNFs.”

The ZNF genes can modify genetic activity and expression without altering genetic information in any way, the researchers explain. They are thus considered to act “epigenetically,” meaning that they communicate environmental data to a person’s genes without any changes to DNA structure.

Dr. Lomniczi’s team found that the aboundance of some ZNF genes, including GATAD1- and ZND573-encoding RNA decrease during the transitional stage that precedes puberty in nonhuman primates — the time during which the “neurological brakes” are released and hypothalamic genes start activating. By increasing the amount of GATAD1 or ZNF573 in the hypothalamus of prepubescent female rates, they could delay puberty’s onset in these rodents.

 

holocaust survivors

Holocaust survivors encode trauma in their genes and pass it on to offspring

It seems environmental cues like smoking, fat intake, even trauma cause alterations to gene activity and expression, all while keeping the DNA sequence intact. Epigenetics is the study of such genetic alterations caused by physiological and psychological environmental exposure and the big question in the field right now is whether these genetic modifications are passed down from one generation to the next. One recent study seems to suggest that epigenetic modifications are indeed inheritable.

Holocaust survivors, for instance, passed down genetic changes associated with stress disorder (the modification was there initially for obvious reasons) to their children. These alterations were not witnessed in the control group and mark the first evidence “of transmission of pre-conception stress effects resulting in epigenetic changes in both the exposed parents and their offspring in humans,” said Rachel Yehuda, the led researcher.

holocaust survivors

Image: Euro Jew Cong

Yehuda and colleagues sequenced the genomes of  32 Jewish men and women who had either been interned in a Nazi concentration camp, were exposed to torture or persecuted (sometimes all situations applied) during the WWII. The researchers then looked at the genes of the children of the Holocaust survivors, specifically those known to cause stress disorders. Finally, the results were compared with the genes of Jews and their families who lived in the same period, but outside of persecution zones.

“The gene changes in the children could only be attributed to Holocaust exposure in the parents,” said Yehuda.

The most famous illustration of epigenetics is the unfortunate Dutch Hunger Winter, which lasted from the start of November 1944 to the late spring of 1945. During this time, West Holland was still under German control. A German blockade resulted in a catastrophic drop in the availability of food to the Dutch population. At one point the population was try­ing to survive on only about 30 percent of the normal daily calorie intake. They ate anything they could get their hands on; grass, tulip bulbs, book covers. By the time Holland was liberated in May 1945, some 20,000 people had died of starvation. Epidemiologists have been able to follow the long-term effects of the famine, but what they found completely blew their minds.

Mothers well fed around the time of conception, but malnourished only for the last few months of pregnancy gave birth to babies to smaller babies, on average. On the other hand, mothers who were malnourished for the first three months of pregnancy, but where then well fed (the blockade was lifted) were likely to birth normal-size babies. The fetus “caught up” in body weigh, sort of speak. That’s pretty straightforward so far, but in the course of the decades doctors have been following the babies they found those  who were born small stayed small all their lives, with lower obesity rates than the general popula­tion, despite having access to as much food as they wanted. That’s not all. The children of the mothers who had been malnourished only early in their pregnancies had higher obesity rates than normal. Then, some of the same effects were observed, to a lesser degree, in the children of those who had been born in those troubled time, that is to say, the grandchildren of the malnourished mothers.

But passing down epigenetic changes to offspring is still a controversial idea. It’s an established fact of science that only genes from DNA get passed on, since the genetic information in sperm and eggs shouldn’t be affected by the environmental cues that cause chemical changes in the working genes. Once fertilization occurs, any epigenetic change is thought to be wiped clear. More and more evidence seems to point otherwise. For instance, a study investigated the mechanism that transfers starvation response to future generations – as in the case of the Dutch Hunger Winter – by looking at worms. The researchers discovered that the starvation-responsive small RNAs target genes that are involved in nutrition and that these became inherited by at least three subsequent generations of worm specimens.

Florida carpenter ant workers: minors (left) and majors (right). Image: MELANIE COUTURE AND DOMINIC OUELLETTE

Worker ants doubled in size by scientists to demonstrate epigenetics

Florida worker ants doubled in size after scientists performed chemical changes to their DNA. The ants were not genetically modified per se, not in the conventional sense that implies altering their code. Essentially, the ants were exposed to a chemical, environmental changes that mimicked those found in their colony and which lead to ants of various sizes and behaviors despite sharing the same genes – a perfect example of epigenetics.

Shaping life

Florida carpenter ant workers: minors (left) and majors (right). Image: MELANIE COUTURE AND DOMINIC OUELLETTE

Florida carpenter ant workers: minors (left) and majors (right). Image: MELANIE COUTURE AND DOMINIC OUELLETTE

Epigenetics is the new discipline that is revolutionizing biol­ogy. Whenever two genetically identical individuals are nonidentical in some way we can measure, this is called epigenetics. When a change in environment has biological consequences that last long after the event itself has vanished into distant memory, we are seeing an epigenetic effect in action. In other words, who we are today (personality aside) can’t be described by genetic code alone – there’s also something else at play. This is why scientists often cite two entities that are genetically identical but nonetheless different as products of epigenetics.

The most famous illustration of epigenetics is the unfortunate Dutch Hunger Winter, which lasted from the start of November 1944 to the late spring of 1945. During this time, West Holland was still under German control. A German blockade resulted in a catastrophic drop in the availability of food to the Dutch population. At one point the population was try­ing to survive on only about 30 percent of the normal daily calorie intake. They ate anything they could get their hands on; grass, tulip bulbs, book covers. By the time Holland was liberated in May 1945, some 20,000 people had died of starvation. Epidemiologists have been able to follow the long-term effects of the famine, but what they found completely blew their minds.

Mothers well fed around the time of conception, but malnourished only for the last few months of pregnancy gave birth to babies to smaller babies, on average. On the other hand, mothers who were malnourished for the first three months of pregnancy, but where then well fed (the blockade was lifted) were likely to birth normal-size babies. The fetus “caught up” in body weigh, sort of speak. That’s pretty straightforward so far, but in the course of the decades doctors have been following the babies they found those  who were born small stayed small all their lives, with lower obesity rates than the general popula­tion, despite having access to as much food as they wanted. That’s not all. The children of the mothers who had been malnourished only early in their pregnancies had higher obesity rates than normal. Then, some of the same effects were observed, to a lesser degree, in the children of those who had been born in those troubled time, that is to say, the grandchildren of the malnourished mothers.

Scientists have later understood that these are epigenetic changes, and we’re only recently truly coming to understand how these work. This latest research that studied epigenetic changes in Florida carpenter ants (Camponotus floridanus) is a prime example.

Ant colonies are fantastic social networks, where the division of labor is essential to its survival and greater good. Queens pump the eggs and workers perform the chores and tasks essential to the ant community. The workers themselves can be either minor or major. The minor workers can be less than 6 mm long. They rear the young and forage for food. The major workers are twice as long and act as guards, protecting the colony. However, queens and workers are all highly similar genetically, but they’re extremely different in size and behavior.

Again, genetic code alone wasn’t enough to explain what was happening here and a team at McGill University in Montreal suspected DNA methylation was at play – the addition of chemicals to DNA. The idea is that the environmental factors stem the discrepancies between the worker ants – some will receive more or less food, as well as different care.

To test this idea, Sebastian Alvarado, lead author on the paper, added chemicals which promote or curb methylation throughout the genome. Increase methylation led to more minor ants, while reduced methylation produced more major ants, as reported in Nature.

“We have provided a biological mechanism that can explain that difference” between major and minor workers, Alvarado says for Science.

Eventually, the researchers nailed some of the genes whose activity promotes growth. One of these is was the epidermal growth factor receptor (EGFR). When the gene was blocked, larger workers were produced. But what’s really bugging the researchers is that it’s not only about growth – it’s also a case of behaviour. Minor workers are care givers, while major workers are aggressive warriors. “It would be interesting to see if a change in DNA methylation also changes their behavior,” Alvarado says. This is what they’re working on now.