by Claudia Ghezzou Cuervas-Mons
We have all experienced first hand, or from someone close to us, what dealing with mental health disorders feels like. Mental health is one of the biggest causes of suicide worldwide and can often lead to other health complications, such as altering hormonal balance and sleep cycles, increased risk of stroke and heart disease, among others. Depression is the second leading cause of disability worldwide, and estimates predict that 1 in 6 people globally have experienced some type of mental health problem. The stigma that has gone hand in hand with these disorders is slowly dissipating, allowing for wider efforts to study the origins of these diseases.
How is epigenetics related to mental health and psychiatric disorders?
We know certain brain regions are associated with certain cognitive and behavioural processes. The cellular makeup of these regions also controls specific functions. Studying the cellular and functional configuration of brain regions has made easier the understanding of normal brain functions and the systems that give rise to it.
In neuropsychiatric diseases, these systems and cellular populations are affected, preventing normal brain functions from taking place.
Here is where the epigenome, all the epigenetic changes on our DNA, has a pivotal role, ensuring the restoration and correct maintenance of the cellular landscape, responding to environmental changes, and trying to adapt the brain systems so they work as they should. When the epigenome doesn’t respond correctly to environmental changes and cues, the brain organisation is further disrupted and leads to perturbed states. In this way, signatures present in psychiatric conditions help us understand the disease state, as well as the healthy epigenome.
Epigenetic alteration of gene expression has a pivotal role in the development of psychiatric disorders. The study of the role of epigenetics in mental health is bringing light into understanding the mechanisms underlying such detrimental processes.
How some people develop certain psychiatric disorders cannot be explained by only contemplating the Mendelian inheritance laws (our inherited genes). This is, at many levels, determined by our genetic material and how this genetic material is then regulated and controlled by the epigenetic mechanisms. Our cells’ morphology, size, interactions, distribution; all of it affects their functioning. The complex cognitive and behavioural processes we experience as individuals, ultimately boil down to what happens at a molecular level.
The strategy of the genes, Conrad Hal Waddington, 1957
Mapping and comprehending the cellular distribution within our brain, how our epigenome organises, is important to understand how it dictates healthy and disease states. For example, the epigenetic landscape of neuronal cells and non-neuronal cells across brain regions varies, as well as it will differ from other cellular landscapes within our bodies. This implies, that different functionality entails differential genetic and epigenetic makeup.
Besides the inherited developmental organisation of our cells, exposure to risks factors at early age shape how our epigenome organises. That can lead to harmful effects and sometimes mental health diseases. Such risk factors range from stress, adverse events, unhealthy dietary regimes, and developmental toxins such as lead. They influence the pathogenesis of some mental disorders, but whether they induce the disease or increase the chances of developing the disease, is still unknown.
In spite of that, a healthy lifestyle, tailored to what our epigenome needs, will help our cells to counteract negative changes and to function as they are programmed to in a healthy state. Awareness of our individual needs and our cellular needs, gives us the chance to adjust our lifestyle choices towards improved beneficial outcomes.
The epigenetic variability giving rise to cellular diversity
A recent study by John Hopkins researchers found that epigenetic diversity across four important brain regions linked to psychiatric traits have characteristic epigenetic organisation. What does that mean?
Their data supported a believed link between neuropsychiatric traits and genetic signals being brought ‘together’ by the epigenetic organisation. They observed increased epigenetic diversity than expected across 12 million base pairs (out of 3 billion) of the genome. Interestingly, these diverse landscapes were most differentiated and characteristic in neurons from a brain region called nucleus accumbens; which plays a central role in our reward circuitry.
“We do know that both epigenetic and genetic changes contribute to the problem of cells not doing what they’re supposed to do,” Andrew Feinberg, co-author of the study.
But if that was not surprising enough, they also found that epigenetic changes correlate with the genetic changes associated with addictive behaviours, schizophrenia, and neuroticism. The epigenetic variations they observed significantly varied across brain regions and co-located across areas rich in inherited genetic signals linked to psychiatric disorders.
This research leads the way for further exploration of the link between genes, epigenetics, and psychiatric disorders. More neuroepigenetics studies may now explore the brain regions with higher epigenetic diversity and how it varies across individuals with and without psychiatric disorders.
Epigenetics of Schizophrenia
Schizophrenia, a long term mental disorder, causes an alteration of the patient’s ability to differentiate delusion and reality; psychosis. In many instances, hallucinations are present, in which the patient is unable to establish whether they are real experiences. Much evidence has been pointing towards a key role of epigenetic mechanisms in the pathogenesis of Schizophrenia. One such epigenetic mechanism that has been studied is the reelin promoter, a fundamental player in correct development of GABAergic neurons in the brain. Hypermethylation of this promoter, adding many methyl tags to it, make it less active, downregulated, and disrupt its role in developmental processes.
Some other methylation changes occur in other GABAergic genes such as RELN and GAD67. GABA is a principal neurotransmitter in the brain, which has an inhibitory action on the neurons it projects to. What is believed is that the epigenetic changes in these genes alter the expression of proteins; it disrupts the amount of GABA cells produced by these genes.
Epigenetics of Depression
Depression affects more than 300 million people globally. This mental health disorder debilitates and disrupts the individuals daily routines, and in many instances leads to suicide. The current research is majorly focused on animal models that explore the origins of the disease. These studies suggest several cofactors leading to the pathology of the disease. One such factor being epigenetic modifications, that induce changes in gene expression and accessibility to our genetic material, and in which stress has a central role triggering some of these responses on our epigenome.
Epigenetics of Addiction
Addictive behaviours are regulated by the reward pathway in the brain. These pathways are dysregulated and taken over by drugs of addiction. What remains yet a mystery is how addictive behaviours persist long after drug abstinence, leading to higher chances of relapse. Some studies point that, indeed epigenetic changes induced by the consumption of drugs, are in part at fault of maintaining an altered epigenetic landscape prone to dysfunction of the reward pathway. One such example is the effect of cocaine use on FosB, increasing its methylation rate within half an hour of drug use. FosB activation by cocaine in turn alters other molecules and genes, such Cdk5, and affects the normal functioning of chromatin remodelling for genes involved in addiction maintenance. All this scientific terminology ultimately means that drug use alters the epigenetic machinery in ways that induce prevalence of addictive behaviours, due to the remodelled logistics of the epigenetic components, benefiting genes that increase reward related behaviours.
Conclusion
These mental disorders share the fact that their occurence cannot be attributed to genetics alone, but what is more likely to trigger the disorders may be a combination of genetic predisposition, epigenetic alterations, and environmental changes and risk factors. Making sense of the role of epigenetics in disease is key to finding better therapeutics and ways to tackle these diseases, and only by further exploring our epigenomes may we find the answers needed to inform new therapeutic strategies.
