Environmental Influences on Gene Structure May Be Transmitted to Offspring
It has been thought that one fundamental principle of genetics is that the impact of environment factors cannot be passed from one generation to the next via the genetic code. New data suggest this may not be true.
In an emerging field called epigenetics, researchers are finding that while the impact of environment and life experiences is not registered in DNA sequences, environmental factors can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment. When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.
Adverse early life experiences can lead to lifelong downregulation of the production of brain-derived neurotrophic factor (BDNF), which is necessary for long-term learning and memory as well as neural and glial health and survival, and of neurogenesis (the production of new neurons for the hippocampus, a process that persists throughout adulthood).
A similar process occurs in adult animals. For example, repeated defeat stress, when a rodent is repeatedly defeated by a larger, more dominant rodent, can lead to the appearance of depressive-like behaviors and a reduction in hippocampal BDNF. The changes in BDNF and behavior are mediated by histone dimethylation, which persistently suppresses hippocampal BDNF. If antidepressants are given to the rodents during defeat stress experiences or if BDNF decrements in the hippocampus are prevented by selective molecular genetic manipulations, the animal does not exhibit the depressive-like behaviors. However, the epigenetic mark of dimethylation of a specific histone is not reversed, presumptively representing a neurobiological scar conveying ongoing vulnerability to defeat-stress-like behaviors in the animal.
Epigenetic alterations can be manipulated pharmacologically
DNA methylation and histone acetylation and de-acetylation had been thought to leave an enduring mark on DNA, but it is now known that DNA de-methylases, histone de-acetylases and histone de-acetylase inhibitors can be used to make DNA harder or easier to transcribe. The anticonvulsant valproate is a potent histone de-acetylase inhibitor, enabling acetyl groups to remain on histones and thus rendering the DNA in those areas more readily transcribed. In animal studies, valproate is given during the extinction of a conditioned response, such as the avoidance of an environment associated with a shock stress, and facilitates extinction learning and increases in the amounts of BDNF transcribed and synthesized. Thus valproate enhances extinction learning via epigenetic mechanisms.
Epigenetics is a new paradigm for understanding how apparently genetic effects are really mediated by the environment. A good example is found in the instance of rat pups reared by an inexperienced and inadequate mother who repeatedly drops, drags, or even tramples them. This early adverse experience leads to an increase in DNA methylation and a lifelong reduction of BDNF levels in the forebrain, as seen in adolescent and adult animals. When female rodents who were reared by inadequate mothers produce a third generation, these offspring also exhibit a reduction in BDNF in their forebrain associated with increased methylation. It would be expected that this reduction in BDNF would be based on the repetition of the behavioral repertoire of the inexperienced mother, and the methylation marks would be re-induced by adversities occurring in the first weeks of the rat pup’s life. However, a publication by Roth et al. (2009) in Biological Psychiatry found that even when the third-generation rat pups are cross-fostered and reared by a highly competent mother, the methylation of the DNA promoter of BDNF remains.
Since originally the DNA methylation was not thought to be transferred across generations, one interpretation of these data was that in utero anxiety experiences were sufficient to re-induce the methylation. However, it now appears that the alternate explanation is possible, and that DNA methylation marks are somehow transcribed directly to the offspring.
Researcher Eric Nestler has also raised this possibility after finding similar evidence of transgenerational transmission of DNA methylation and other epigenetic markers.
Similarly, in a plenary lecture at the American College of Neuropsychopharmacology in December 2009, researcher Andrew Feinberg suggested that this process may not only be routinely possible, but might shed light on theories of evolution. Darwin had developed the principle of selection of the fittest based on the occurrence of rare mutations in the DNA sequence. Feinberg suggests that evolutionary theory be revised to include the adaptive selection of those with the best epigenetically-based adaptations to the environment. This concept relies on the possibility that epigenetic mechanisms are accurately transferred across generations, a process originally proposed by French scientist Jean-Baptiste Lamarck around the turn of the 19th century and subsequently scorned by the rest of neuroscience.
In contrast to Lamarck’s ideas, the epigenetic mechanisms posited by Feinberg are based on the selection for positive adaptations, which Feinberg believes occur on a frequent or random (stochastic) basis. Positive epigenetic adaptations to the environment would be selected for, explaining the more rapid evolution of many species than would be expected based on rare genetic mutations alone.
Should these views of epigenetics prove valid, they would not only change the field of genetics and evolutionary neurobiology profoundly, but they would also forge a new understanding of environmental impacts on the development of mental illnesses and suggest the potential for radically new conceptions of treatment. There are known substances that prevent DNA methylation, and some histone de-acetylase inhibitors are even routinely available in clinical practice in the form of valproate and butyrate. Therefore, there is great opportunity for attempting to modulate and alter what were previously considered lifelong epigenetic vulnerabilities contributing to the onset and progression of the major mental disorders.
None of our currently available treatments to date has reversed any of the primary pathophysiological aspects of illness vulnerability, and patients with the recurrent unipolar and bipolar affective disorders and with schizophrenia require lifelong treatment in an attempt to suppress illness and prevent recurrence. The new conception of the role of epigenetics opens up the possibility of considering treatments that may ultimately reverse some of the basic illness vulnerabilities (based on the environment and epigenetics) and lead to what might be considered curative treatments.
An early example of potential therapeutic approaches using epigenetic manipulations was noted in the last issue of the BNN in the study reporting positive effects of the histone de-acetylase inhibitor valproate on a variety of target symptoms in autism.
In fragile X and a variety of other genetic illnesses with major psychiatric manifestations, there is an excess in activity of the methylating enzyme MECP2. This excess results in a lifelong alteration in the set point of the ratio of excitatory (glutamatergic) to inhibitory (GABAergic) activity in the central nervous system in the direction of deficient excitation and increased inhibition. To the extent that this epigenetic mark could be inhibited, there is potential for amelioration of many of the symptoms of fragile X-related syndromes, even in adults who have experienced long-term psychological and mental deficiencies. This also raises the possibility of primary prevention in those who might be tested and found vulnerable to the development of a fragile X-related syndrome. Early application of inhibitors of the hyperactive methylating process could prevent the major manifestations of these syndromes altogether.
Environmentally-induced epigenetic alterations leading to the development of psychiatric disorders would offer a potential explanation for why no genes of large effect have been identified in the major psychiatric disorders despite an expensive and wide search across the entire human genome. While some mental illness vulnerability factors may, in fact, be encoded in the inherited variations in gene sequence, epigenetic processes may play an important role as well. There is increasing agreement that most complex psychiatric illness involve interaction of multiple gene and environmental vulnerability factors.
The powerful nature of epigenetic alterations in the developing animal is most readily seen in the differentiation of different organ systems in a developing fetus. That is, every cell in the body has the same DNA sequence, so it is by some other mechanism that some cells become liver cells and others become muscle or brain cells and these cells remain liver, muscle, or brain cells each time they divide and replicate. Thus, cell fate appears to have a primary epigenetic mechanism and epigenetic mechanisms now appear to have a major role to play in adult learning and memory.
While this new view of epigenetics yields further evidence of the positive viewpoint that one’s genetic inheritance is far from an absolute determinant of ultimate behavior, there may be a darker side to this equation as well. While the idea that adverse interactions with the environment may be transmittable across generations in the form of epigenetic mechanisms can offer greater hope for ultimate therapeutic interventions, it also allows for the possibility that aberrant behaviors could be passed down through multiple generations.
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