Epigenetics…let’s get started.
The text below refers to laboratory results published back in 2011. However, those results are a good example of what epigenetics can mean to our lives. If, after reading the post, you’re more confused than before, don’t worry – even senior scientists working in this field for a long time can be surprised by the experimental results related with epigenetics!
How long did your grandparents live?
If you are aware that genes we inherit from our ancestors can help us be handsomer, smarter, more athletic or healthier; or even that the proper combination of genes and the right choices in lifestyle can dictate our life expectancy, you should still prepare to be surprised: scientists from Stanford University and Harvard Medical School have discovered that we can inherit more than genetic material from our parents and that such inheritance can augment our longevity. Yes, our parents and grandparents can help us live longer.
Or at least, so it happens in model organisms. The study published back in october 2011 by Greer et al. in Nature, used the nematode Caenorhabditis elegans, a very small and transparent roundworm of great utility in development and ageing research. This simple form of life of about 1mm in length is cherished by researchers as it is easy to grow in the lab and its genes can be manipulated as desired. The short lifespan of two to three weeks was a great advantage for this study. For a while, it was known that the longevity of these worms could be prolonged by removing (or mutating) a gene or a set of genes in the worm genome. Now, scientists asked if the increase in longevity could still be observed when the genes were “put back in place”. Confusing?
Well, it is at least complicated. In other words, what the scientists wanted to know was: can specific events experienced by parents be passed as inheritable traits to their offspring? In this case, the event parental worms went through was the increase in longevity engineered in the laboratory. The genetic alterations introduced to create the extra lifespan were then removed so that the following generations of worms had “lost” the mutations and become “normal” worms again. The results were beyond dispute: the descendants lived longer than descendants of normal unmodified worms up to the third generation. What researchers learnt form this study was that circumstances or events lived by great-grandparents conditioned the lives of the new generation of worms.
The phenomenon behind these observations is epigenetics. Meaning something like “above genetics”, epigenetics refers to changes in the characteristics of an organism that do not alter the genetic code but can affect the behaviour of genes and be passed down through generations. These changes are known to scientists and target well-defined features of the DNA molecules and its associated proteins, rather than the DNA sequence itself. In the case of the worms, the offspring benefited form a lab-induced increase in longevity that occurred at a specific point in time, which was the period of the lives of their great-grandparents. Three generations later, the memory of those early worms was still alive in their descendants.
Epigenetic inheritance is common to higher organisms, including mammals. So, similar processes can occur in humans. In principle, one particular person or generation can be “marked” by specific events or by a certain environment that changes their traits (but not their DNA sequences) to novel ones; the event can pass and the environmental conditions change, but the new traits can persist through generations. In this unexpected way, our existence in the present day can be ruled by past epochs. Who were our ancestors? How did they behave and what did they eat? How long did they live? If we want to understand why we are who we are, it’s in our family tree.
Cancer’s new signatures:
Epigenetic modifications are conserved among various metastases in the same person.
Today’s EpiPost focuses on a new discovery concerning prostate cancer and its metastases. The report published in Science Translational Medicine (23rd January 2013 ) highlights the need for personalized medicine by showing that the patterns of epigenetic modifications vary considerably between lethal prostatic tumours from different men but are maintained within the tumour and metastases in the same person.
Epigenetics is the layer of genomic regulation that is not due to the sequence of As, Ts, Cs and Gs in the DNA molecule, but instead relies on chemical marks found in nuclear DNA and its associated proteins. These epigenetic marks that sit on DNA, namely the methylation mark, are very relevant from the point of view of physiology, as they may shape to the way cells responds to stimulus, both from outside, and from inside the cell itself. In recent years, scientists have observed that tumours display their own patterns of DNA methylation and those differ from the ones found in the “normal” cells of the same person. This observation led to the question: can DNA methylation be used as a diagnostic biomarker for cancer?
So far, the general belief that DNA methylation patterns varied too much in each patient’s widespread cancers procrastinated the development of diagnostic strategies or even therapies. Now, with the help of new biochemical and computational technologies, scientists from the Johns Hopkins University, in Baltimore, USA, made two seminal observations that may change this view: first, that the DNA methylation patterns were considerably altered between tumours from different individuals; and second, that tumours and metastases from the same individual had identical DNA methylation patterns. For this analysis, the samples were obtained from autopsies of men who had died of metastatic prostate cancer. Both samples from the various metastases, as well as samples from normal tissues were collected for genomic comparisons.
The results led the scientists to conclude that each cancer evolves to acquire its own characteristic signature of DNA modifications, and that this epigenetic signature is maintained at sites of metastases. This observation has a close parallel to what is known about genetic alterations of tumours, which are also stable within each individual. As with genetic alterations that contribute to the onset and dissemination of cancer, epigenetic changes are also to be taken into account when investigating the events leading to cancer progression.
The new data revealed that new biomarkers of aggressive cancers lie in the epigenetic landscapes of each patient’s cancer cells. Scientists believe that this knowledge will help in the early identification of these forms of cancer and may possibly contribute to the development of therapeutic strategies directed at each person’s specific cancer epigenetic signatures.
Chronic pain can be marked in the DNA
The work was published in the open-access journal PlosOne. To model pain, scientists injured nerves in the tight of laboratory mice through surgery. The purpose of the study? To understand if the lesion remains in the DNA of cells as a mark.
The research showed that epigenetic marks can be found in the DNA of cells from brains of mice suffering from chronic pain. Epigenetics comprises the chemical marks in the DNA and associated proteins that are the product of signals and stimuli arising from different sources. In the same way as each cell is characterized by its genes (genetics), it is now clear that cells are also characterized by the chemical modifications in those genes (epigenetics). Even if epigenetics cannot change the sequence of genes in the DNA molecule, it can control the way genes are “read”. In this experiment, peripheral nerve injury led to epigenetic alterations in the brains of the mice, at the level of DNA, as if to remind the animals of the lesion suffered 6 months before.
It is not clear yet which consequences originate from the epigenetic marks in specific regions of the brain. To better understand the mechanism observed, scientists induced symptom relief, to some extent, by means of exposing the mice to modified cages (a procedure somehow similar to a series of physiotherapy sessions). The changes in the symptoms were associated with changes in the epigenetic marks of the DNA molecule in the brain cells. Scientists learnt that the marks in the DNA could be related by the levels of pain.
In the future, will this information be useful to those patients suffering from chronic pain, regardless of its cause? The authors of this study are optimistic about the future and believe that one day it will be possible to treat pain if the epigenetic marks in the DNA are modulated by clinicians. And even if the treatment of pain is far from reality, these new observations can start by serving another purpose: that of quantifying pain. Currently, assessing pain in complex due to subject to subject variability. However, establishing a more objective method of quantification could be beneficial for the correct diagnosis and treatment of various pathologies. This new study can be the basis for a new, epigenetics-based, quantification method for pain.
From the brains of honeybees, we learned that epigenetics can control social behaviour and career changes.
While developing, one sister bee can become a queen, while the other sister will be a worker for her entire, considerably shorter, life. How is this achieved if these sisters share the same genetic code? At birth, all honeybees look identical and it is not clear which one will become a queen. In contrast with human royalty, bees do not inherit royal “blood”, meaning that the genes they carry will not dictate their social fate. A paper published back in October of 2012 has revealed that the secret is epigenetics, the alterations in DNA and its associated factors that are independent of the sequence of DNA itself. We all know that DNA is made of As and Ts, Cs and Gs, and even if we do not know what they mean, we understand that these letters form codes and those codes control the way organisms function. While studying the brains of honeybees, scientists have discovered that the DNA letters may be shared by a queen and a worker in the same hive; however, there are particular changes found in those letters that make all the difference*. Those are the epigenetic changes, in particular the epigenetic mark called DNA methylation.
Whereas the difference between queens and workers could not be explained in the referred paper, differences between workers with different roles in society became more obvious. For that, scientists compared the brains of nurses with the brains of foragers to conclude that DNA methylation was different between these two subcastes. More importantly, when foragers were compelled to switch to nurses, DNA methylation switched as well. The authors concluded that there are epigenetic patterns associated with the different subcastes and that those are reversible.
There are at least two reasons for this to be one of the most important pieces of work published recently, and you may be guessing why… One, these observations are fundamental in that they explain the principles through which different characteristics – behavioural, morphological, of lifespan – can arise from the same sequence of DNA. Two, they are seminal because they showed for the first time that well-defined, securely-established patterns of behaviour are not free from change: epigenetics carries the key to life’s turning points, which may include your long-awaited career change.
*The conventional definition of Epigenetics implies heritability through generations; here, the concept is used in a more “relaxed” way, meaning that the need for inheritance is not stressed.