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Epigenetics and the Influence of our Genes

Very interesting video about Epigenetics with clear pronunciation.

 

Script

Nine years ago, I found myself in a doctor’s office, contemplating the nature versus nurture debate from a fresh perspective. You see, I had been trained as a geneticist and had spent my career manipulating DNA and seeing the profound consequences in a lab setting, so I’d always put my money more on the nature, or the genetic side of the debate.

But, as my doctor revealed to me that I was pregnant with identical twins, I realized that my convictions were about to be put to the test. For starters, we had not budgeted on two daycare bills at once. So I kind of half-jokingly started to wonder what would be the consequences maybe, if we just sent one twin to daycare and maybe just kind of tuck the other one in my office drawer during the workday. Despite their identical DNA, I somehow doubted that things would turn out all that well for the twin in the office drawer.

Identical twins have had a profound impact on scientists’ understanding of nature and nurture. Studies on identical twins who were separated at birth and raised in separate households have helped us understand different traits that are more affected by nature, or DNA, versus nurture, or the home environment.

For example, some traits, like IQ or criminal tendencies, are more affected by your DNA than the house that you grew up in. On the other hand, other traits, like depression in men, or your preference for a particular political party, are more influenced by your environment than by your genes.

So what about identical twins who are raised in the same home environment? Their nature and their nurture are almost the same. And yet, any parent of identical twins, myself included, can quickly point out differences in their children. One twin may have more of a preference for certain types of foods, or may have more aptitude for a certain sport or musical instrument.

And sometimes, health differences can arise in these children. For example, there are reports of autism, or asthma, or bipolar disorder arising in one twin at a young age while the other one remains unaffected.

How do we explain these differences, given that the DNA is the same in these children? And for the large part, their home environment has been the same too? Well, it turns out that some of these differences can be explained by a third, very powerful influence on our lives, besides nature and nurture. This is epigenetics.

I’m going to talk to you today about what epigenetics is and how it impacts your life, even if you’re not an identical twin. So before we talk about epigenetics, we need to consider our DNA and how it fits into our cells because, believe it or not, of the 50 trillion or so cells in your body, each one contains about six linear feet of DNA. I mean, if we were to stretch it out, it would be about as tall as a pretty tall man.

So how in the world do we fit that amount of genetic material into something the size of a cell nucleus, which is 400,000 times smaller? Well, the answer is that we do it by wrapping our DNA around clusters of proteins called histones. You can think of histones sort of like molecular spools. And there are about 30 million of these spools in each of your cells. So this helps explain how you fit such a tremendous amount of DNA into a small space. Now we call this combination of histones and DNA, chromatin.

And while chromatin solves this tremendous packaging problem that the cell has, it also presents a new one for the cell. And this is one of DNA accessibility because keep in mind that the functional units of DNA are actually the genes encoded in it. These are the instructions for the cell. These are what tell the cell what to do and who to become and yet, when these genes are tightly compacted into a chromatin structure, the cell is unable to read them, they might as well not even be there. This is where epigenetics comes in.

So ‘Epi’ meaning ‘on top of’ and ‘genetics’, your ‘genes’, literally refers to a set of instructions that sits down on top of our DNA and our histones. Epigenetic marks are small chemical tags which sit down on our chromatin and can help instruct it whether to compact or decompact. And those instructions can then affect how the cell reads the underlying genes encoded in the DNA.

So, to show this schematically, some Epigenetic marks, shown here in red, can help condense chromatin. And when they do this, they obscure the underlying genes, preventing the cell from being able to read them. They turn those genes off.

Other Epigenetic marks, shown here in green, can help decondense the chromatin. And when they do this, the gene becomes accessible to the cell, the cell is able to read it and turn it on. Now these types of epigenetic marks are profoundly influential to our biology.

Consider, for example, what is it that makes our cells different from one another? What makes them look and behave differently? What is it that makes a muscle cell, for instance, look different from a neuron? After all, these cells contain exactly the same DNA but it’s their epigenetic instructions that help tell them which genes to turn on and which ones to turn off. And with those different genes at play, these can become very different cells.

So you might be wondering when does all this epigenetic information get laid down on our chromatin? And the answer is that much of it happens during our embryonic development. So interestingly, when you were first conceived, and you were just comprised of a few, undifferentiated embryonic stem cells, which had the potential to become any cell in your body, your chromatin didn’t have many epigenetic marks on it. It was only as your cells began to divide and received signals and information from surrounding cells, that the epigenetic marks began to accumulate and then the genes began to get turned off and turned on, and the muscle cell became very different from the neuron.

This brings me to a really important point about epigenetics. And that is that, epigenetic marks can be influenced by the environment. And when I say environment, I don’t just mean those surrounding cells that tell a neuron to become a neuron. I also mean, the environment outside of the developing embryo. So the food that the mom eats, or the pre-natal vitamins that she takes, or the cigarettes that she smokes, or the stresses that she encounters at home or at work, can all be transmitted as chemical signals through her bloodstream to her developing fetus, where they can get laid down as epigenetic marks that affect the fetus’ own genes and long-term health.

Now this has been shown experimentally in mice. Mice contain a gene called agouti, which makes them obese and yellow and susceptible to diseases, like cancer and diabetes. This gene and these traits can be passed down from generation to generation through DNA so that an agouti mother will give rise to a fat, yellow, disease-susceptible offspring, if that offspring contains the agouti gene.

Now here’s something interesting about the agouti gene. It can be turned off, if silencing epigenetic marks accumulate around it. So, if a pregnant agouti mother is fed a diet which is supplemented with these silencing epigenetic marks, those marks will be chemically transmitted to the DNA of her embryo, where they’ll accumulate around that agouti gene and effectively turn it off. Her embryo will maintain those marks. So it will be born and grow up to be an adult mouse that’s thin, and brown, and healthy.

Even though this mother is genetically identical at the DNA level to both sets of this offspring, you can see that the diet that she consumed during her pregnancy can affect the health and appearance of her offspring. This has, of course, implications beyond the mouse world, because studies in humans have shown that women who don’t eat well during their pregnancy, who eat bad foods, will go on to have children who are more susceptible to developing obesity and cardiovascular disease.

Likewise, if women smoke during their pregnancy, their children will grow up to have a greater chance of developing asthma. These correlations between maternal behavior during pregnancy and the long-term health consequences for their offspring are thought to be linked by epigenetics, much as you’ve seen here in the case of mice.

Now another important point to make about epigenetics is that these types of marks can be transmitted not only from a pregnant female to her fetus but also from generation to generation if the marks are put down on our sperm or eggs. So, if you’re in the audience and you’re not pregnant, and you’re not even thinking about conceiving, think about this, because the lifestyle decisions that you make today can still affect future generations.

For example, a long-term study was conducted in Sweden and England that showed that young boys who over-ate or started smoking during their pre-pubescent years, as their sperm was starting to develop, went on to have sons and grandsons with significantly shorter lifespans. It’s believed that the epigenetic marks that were transmitted by their diet and smoking decisions, affected the long-term health of their future generations. This type of epigenetic information, of course, can also be passed through females to their daughters and granddaughters, if the epigenetic marks are laid down on their eggs.

Now this idea of transgenerational inheritance of epigenetic marks is still being debated and studied in terms of humans, but I should add that in non-human organisms, mice, flies, worms, there’s mounting evidence that this theory holds true. In fact, it’s being shown in the lab that over tens of generations, epigenetic marks can be passed down.

Now another thing to know about epigenetics is that they don’t just affect us when we’re a developing embryo, or when the sperm and egg that conceived us were developing, they can also affect us after our birth. And this is particularly relevant as we think about our brains which continue to grow and develop throughout our lives.

Take this example from rats. Rats contain a gene called the glucocorticoid receptor and this gene can be expressed, or read, in a certain region of the rat’s brain. And when it is, it helps the rat cope with stressful situations. So, the more receptor that a rat has in this region of the brain, the better it will handle stress.

Now there are studies that have shown that interactions between a rat mother and her pups during the first week of their life can have long-term consequences for how much glucocorticoid receptor those pups will grow up to have in their brains and therefore how well they will handle stress.

This is how this works. When rat pups are born, their glucocorticoid receptor gene is surrounded by a number of these silencing epigenetic marks. This effectively turns the gene off. And yet, if a rat mother extensively licks and grooms on her pups, basically takes good care of them, during the first week of their life, those epigenetic silencing marks can be removed from the gene. This allows the glucocorticoid receptor gene to turn back on, and it stays on in those pups’ brains throughout their lives. So they grow up to be well-adjusted animals who deal well with stress.

If a rat mother ignores her pups, that glucocorticoid receptor gene will maintain those silencing epigenetic marks, they won’t go away, and they’ll stay in those pups’ brains throughout their lives. These rats will grow up to be very anxious in stressful situations.

This actually brings up a really encouraging point about epigenetics in that epigenetic marks are reversible. So, if you’ve been sitting in the audience cursing your parents and your grandparents for their poor lifestyle decisions, or for the lack of licking and grooming that you received as a baby, take heart, because scientists are making terrific progress in designing drugs that can reverse toxic epigenetic marks to help combat certain diseases. This is especially looking promising in the case of certain cancers which happen to be affected or turned on by aberrant epigenetic marks.

This is how this can work. Our bodies have certain genes in them called tumor-suppressor genes. The job of these genes is to protect cells from becoming cancerous. But if too many silencing epigenetic marks start to accumulate around these genes, the genes get turned off, and they can no longer perform their job of protecting the cell.

So scientists have developed drugs which have undergone FDA approval, and they’re in a clinical setting, which can target these silencing marks effectively removing them from the tumor-suppressor genes and allowing these genes to go back to their job of protecting the cell.

Now think about it. This is a radical departure from traditional cancer therapy. Historically, we’ve always been focused on killing cancer cells. This, however, is taking the approach of restoring cells to their original nature, reminding them of what they’re supposed to do. This type of therapeutic approach is showing great promise in terms of other diseases as well, besides cancer — diseases that are also similarly affected by aberrant epigenetic marks, like diabetes, and lupus, and asthma, and certain neurological disorders, Huntington’s and Alzheimer’s diseases. I’m optimistic that this type of therapy is going to hold great promise for our health in upcoming years, but I should caution that one of the challenges as we go forward is figuring out how to target these drugs toward toxic epigenetic marks while leaving alone the beneficial ones that help maintain our health.

I want to conclude by emphasizing that there are things that we can do now to positively influence our epigenome. It’s not too late — it’s not too late to start eating healthier foods, foods that we already know are good for us, like leafy vegetables, whole grains, avoiding cigarettes, cocaine, stress all of which have been shown experimentally to impact our epigenomes negatively. These are things that you can do to impact your genes and your long-term health. And if that’s not incentive enough, they can also impact the health of your future children and grandchildren.

I think this concept, that we can positively impact our genes, is really profound and empowering because we’ve always worked under the assumption that our genes are set in stone, that they’re beyond our influence. I want to end today by challenging you, and myself, to take the opportunity that we have before us to positively impact our long-term health by treating our epigenome kindly, through healthy lifestyle decisions.

Thank you.

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