March Infant Parent Mental Health Meeting: Epigenetics I

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Barry Lester taught us about epigenetics. He started with reviewing the background of “fetal origins” and the concept of “fetal programming”. Can the study of genes and environment at the cellular level inform us about molecular influences on behavior? The hypothesis states that susceptibility in cardiovascular disease, non-insulin-dependent diabetes mellitus, and the insulin resistancy syndrome, is programmed in utero as a response to fetal malnutrition. This dates to the German starving of Dutch mothers during World War II. There was a relationship between low birth weight and hypertension, 40 years later. The general concept is that reduced fetal growth leads to altered structure and function in the fetus, leading to increased risk for adult disease. During the famine, the fetuses were starving and they wanted to prepare themselves to survive in a famine environment. Instead, the famine ended and the babies were born into adequately nourishing environments. They had adapted their systems to slowed-down metabolism and couldn’t adapt. 

Developmental plasticity enables the organism to change, reprogram structure and function in response to environmental cues. The adaptive significance is that plasticity enables a range of phenotypes. Many studies have replicated this finding. The idea is that your risk of disease depends on the extent to which you are prepared for, or match with, the external environment. Can these effects be produced by environmental insults other than malnutrition? What might be the underlying mechanisms? Could epigenetics provide the molecular basis for fetal programming? What might be the applicability of this model beyond chronic disease to behavior? 

There is evidence that the fetal origins theory relates to the etiology of neurobehavioral problems and mental illness. Low birth weight is related to schizophrenia, depression, and psychological distress.  What is the molecular basis?

Epigenetics has to do with the heritable and stable control of gene expression beyond DNA sequence. It is heritable – can be passed on to successive cells – yet does not alter the genetic sequence, and inter-generational. It is stable and cannot be altered. It is environmentally sensitive. There are critical periods (a lot of this happens in periods of rapid development) and reversible. Epigenetics controls gene expression and transcription, turning off and on the gene. The gene stays the same, but what the gene makes happen is changed. Conrad Waddington (Professor Genetics, Univ. Edinburgh, 1905-1975) described epigenetics as “cross talk” between the gene and the environment. 

Epigenetic changes happen all the time. The field started in cancer. Epigenetic research has since expanded into behavior. Barry’s “favorite example” is that in which the mother is a drug addict and is loaded with addiction genes. If you could turn them off, the baby will inherit the same DNA but will not inherit the addiction. This is pure fantasy but possible. Epigenetics refers to the changes in gene activity, expression, without changing the gene. It can be silenced, enhanced, and change can be transferred to the next generation some of these changes can be reversed. 

The most common mechanism in which environmental influences can produce stable alterations is DNA methylation. (Histone is another one. The outer layer of the package of DNA is histone.) The metaphor is gum on a light switch. Epigenetic changes occur when genes are being replicated. The DNA is transcribing to RNA and that is producing proteins. The amino acids guanine and cytosine hang out at the gene transcription sites – CPG islands. A protein puts little methyl tags on the gene. That is like gum on a light switch; it turns off the gene. 

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The vast majority of behavioral studies are animal studies. When you make the transition to behavior, there are leaps involved. The biggest challenge is that most of the changes in epigenetics are changes in the brain, and it is hard to get human brains. The field is split into the hard-core group that says if you are not dealing with brains, it is no good. The other group is more flexible. Some people look at placental tissue, others blood, and others saliva. 

Michael Meaney is a researcher who has studied the relationship between maternal care and gene expression. What Meany does is show the different kinds of maternal care change gene expression (glucocorticoid system – stress) in the pups, and this changes maternal behavior of the pups as adults, as well as their stress reactivity; and it is inter-generationally transmitted. Michael Meaney divides the rats into low lickers and groomers and high lickers and groomers. It turns out that if you are the offspring of HLG, you become a HLG, and if you are the offspring of a LLG, you become a LLG. The gene has an effect on the hypothalamus and through hormonal changes to the pituitary, then to the adrenal cortex and the production of cortisol. There is also a negative feedback loop. The changes in gene expression occur in the hypothalamus. Meany looks at methylation in the hippocampus. The CPG sites cluster in regions. You can look at the amount of methylation at each of these sites. There are a number of sites where if you are a HLG you have less methylation than if you are a LLG. Your stress reactivity is lower; you are putting out less cortisol if you have less methylation. So if you have less methylation, you are calmer (HLG). The hippocampus is producing less cortisol than if you are a LLG, where you are producing more cortisol and have a more active stress response. 

 

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