Epigenetic Mechanisms in Psychiatric Disorders – Major Depression, Psychosis and Addiction

BASIC GENETIC CONCEPTS - DNA, HISTONES, NUCLEOSOMES, CHROMATIN AND CHROMOSOMES

• Chromosomal DNA is packaged inside microscopic nuclei with the help of histones.
• DNA is complexed with histones to form nucleosomes

• Each nucleosome is composed of DNA wound 1.65 times around eight histone proteins. Nucleosomes fold up to form a 30-nanometer chromatin fibre averaging 300 nm in length.
• The 300 nm length fibres are compressed and folded to produce a 250 nm wide fibre, which is tightly coiled into a chromosome’s chromatin. This allows the 3 billion nucleotides in the mammalian genome to be stored within the microscopic space that is the cell nucleus.

• The chromatin nucleosome is in a continuous remodelling state: from activation (open to transcription) to inactivation (closed to transcription).
• Histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) are two enzymes that help control the active and inactive chromatin state, respectively.
• Together, HAT and HDAC affect gene transcription rates by adding an acetyl group (promotes gene expression) or removing an acetyl group (promotes gene repression).
• There are also other post-translational modifications, including methylation, ubiquitination, and phosphorylation of the DNA sequence.

EPIGENETIC PROCESSES

Many types of epigenetic processes have been identified—they include methylation, acetylation, phosphorylation, ubiquitylation, and sumoylation. Some of the structural and chemical adaptations to DNA that modify and influence gene expression activity have the following mechanistic components: [Aristizabal et al., 2020]

In particular, methylation and demethylation processes (mediated by DNA methyltransferase enzymes) have emerged as an important investigation area in furthering our understanding of epigenetic modifications.

• DNA can be modified at cytosine and adenine residues by the addition of chemical groups.
• Cytosines can be modified by methylation, hydroxymethylation (hmC), formylation (fC), and carboxylation (caC), while adenines are modified by methylation.

• Nucleosomes can change position to increase or decrease DNA accessibility. Also, nucleosomes can be modified by the incorporation of histone variants and the addition of posttranslational modifications.
• Noncoding RNAs play an important role in transcription regulation and are sometimes considered an epigenetic mechanism. Non-coding RNAs include Micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs)
• MicroRNAs (miRNAs) mediate the recognition and binding of RNAs that become targeted for degradation.
• Long non-coding RNAs (lncRNAs) are associated with other complexes and can activate or repress transcription.
• The addition of chemical groups can modify all RNA nucleotides. The list of RNA modifications includes over 160 other chemical modifications.

The modifications alter the chromatin structure to influence gene expression. In general, tightly folded chromatin tends to be shut down or not expressed, while more open chromatin is functional or expressed.

Imprinting:

Imprinting is the process where one of the two alleles (variants of a gene) of a typical gene pair is silenced by an epigenetic process such as methylation or acetylation. This becomes a problem if the expressed allele is damaged or contains a variant that increases the organism’s vulnerability to microbes, toxic agents, or other harmful substances.

EPIGENETIC BASIS OF PSYCHIATRIC DISORDERS

There is growing evidence of the role epigenetics may play in the etiopathogenesis of psychiatric disorders.[Ptak, 2010]

Research suggests that this is mediated by disease-associated modifications that induce stable and lasting changes in gene expression, then over time, can contribute to the pathophysiology of psychiatric disorders.

• Indirect epigenetic mechanisms are transgenerational—mitotically stable processes—that can alter gene expression levels across multiple generations in various cognitive processes, including neurogenesis, learning and memory, and circadian rhythms.[Nadeau, 2009], [Kim & Kaang, 2017]
• It is unlikely that one specific gene’s altered expression level underlies the cause of a specific psychiatric disorder. Therefore it may instead be the role of chronic environmental factors (e.g. stress, nutrition, infections, medications, and addictions) that directly result in epigenetic-related behavioural changes over the long-term.[Mathers J et al, 2010],[Christensen & Marsit, 2011],[Talikka M et al, 2012]
• Other factors may include direct stochastic events, which provide epigenetic variability of phenotype.[Feinberg & Irizarry, 2010]
•  The Dutch Hunger Winter, a famine period at the end of World War II, was associated with negative metabolic and mental health outcomes in later life. Individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944–45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene than their unexposed, same-sex siblings. The association was specific for periconceptional exposure. [Heijmans et al., 2008]
• Similarly, parental PTSD following exposure to the Holocaust is associated with increased psychiatric risk and reduced cortisol production in the next generation, effects that are most pronounced in children conceived closer in time to the Holocaust. [Yehuda et al., 2007]
• Yehuda et al. reported reduced cytosine methylation within a region of the FKBP5 gene in blood samples from adult offspring of Holocaust survivors, which correlated with reduced cortisol levels at waking. [Yehuda et al., 2016]
• The significance of reduced cortisol may indicate a vulnerability towards lowered fear extinction and habituation in the context of a traumatic event allowing for uninhibited sympathetic activity (via unopposed Noradrenergic activity) and amygdala activation. (Read more in the neurobiology of PTSD)

EPIGENETICS IN MAJOR DEPRESSIVE DISORDER

There is a high degree of co-morbidity between stress and depression, with depressive-like behaviours putatively linked to changes in brain-derived-neurotrophic factor (BDNF) expression.[Brunoni A et al., 2008]

For example, there is a reduction in BDNF expression in response to stress in the hippocampus, hypothesised to be mediated via epigenetic mechanisms.

BDNF is a pro-survival factor that has been observed to have antidepressant efficacy, particularly through its effect on limbic circuits—this forms the basis of the neurotrophic hypothesis of depression.[Duman & Monteggia, 2006]

Human studies have also shown that BDNF expression levels play a therapeutic role in the efficacy of antidepressants.[Castrén & Rantamäki, 2010]

More recently, the TRKB receptor, which is a receptor for BDNF, is the main receptor binding site for the mechanism of antidepressants. [Casarotto et al., 2020]

• Using the chronic social defeat stress paradigm (animal model for depression), it has been shown that histone methylation of the BDNF promoter is increased, thus reducing BDNF mRNA production.[Siuciak J et al., 1997]
• Histone deacetylase inhibitors show antidepressant-like efficacy and show potential in the development of novel antidepressants for treatment-resistant depression. [Fuchikami et al., 2016] 
• Other studies have shown that the absence of the BDNF promoter results in depressive-like symptoms under stressful conditions.[Sakata K et al., 2010]

Gene-environment interactions between the 5-HTTLPR variant and stressful life events influence the risk of developing depression among subjects with one or both short alleles of the 5-HTTLPR variant in a prospective longitudinal study of Dunedin children. Individuals with one or two copies of the short allele of the 5-HTT promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. [Caspi et al., 2003]

Therefore, chronic stress can mediate long-lasting genomic changes (e.g. histone modifications and DNA methylation) that may underlie the aetiology of depression. Overall, the research suggests that the epigenetic regulation of the BDNF gene shapes an individual’s response to environmental stimuli, stress, and even their response to antidepressant treatments.

EPIGENETICS IN PSYCHOSIS

There have been many recent advances in determining the epigenetic changes associated with major psychosis, including schizophrenia and bipolar disorder.[Fusar-Poli P et al., 2013]

Epigenetic modulations appear to play a significant role in major psychoses. Although they have been confirmed in schizophrenia patients [Muntjewerff M et al., 2006] as well in their mothers during pregnancy [Brown A et al., 2007], there are inconsistencies in the data.

The main epigenetic mechanisms are: 

• Longitudinal methylation changes in specific genomic regions have been identified as attributable factors in the conversion to psychosis. This includes genes that are involved in redox metabolism, axonal guidance, and inflammation.[Kebir O et al., 2017]
• Since DNA methylation is postulated to be involved in the pathogenesis of schizophrenia through lowered reelin expression,  DNA methyltransferase inhibitors (inhibit DNA methylation) increase reelin expression levels, which are lowered in schizophrenia. However, DNMT inhibitor research has mainly focused on animal studies, and more human research is required. [Kurita et al., 2012]
• Stochastic (random or uncertain) epimutations are specific to an individual and occur randomly over decades of life, even in the absence of detectable environmental influence. These epimutations are also known as epigenetic drift, which has previously been observed in the genes for dopamine receptor 4, serotonin transporter, and X-linked monoamine oxidase.[Wong C et al., 2011]
• Many of the findings revealed associations with epigenetic modulations of genes regulating neurotransmission, neurodevelopment, and immune function, as well as differential miRNA expression (e.g., upregulated miR-34a, miR-7, and miR-181b). [Smigielski et al., 2020]
• Chronic treatment with the atypical antipsychotic, clozapine, in mice and humans leads to a downregulation of glutamate (mGlu2) receptor expression via a decrease in acetylation at its promoter site, and that it is specifically an increase of histone deacetylase (HDAC2) binding to the mGlu2 promoter that mediates this effect. [Kurita et al., 2012]
• GAD67 promoter region is another promising target region in therapeutic but more research is needed. [Kurita et al., 2012]

Overall, disorders such as schizophrenia and bipolar disorder are phenotypically and genotypically diverse, and therefore, more research is required to determine epigenetic biomarkers for diagnostic purposes in major psychoses.

ADDICTION

Genetic studies have shown that there is a strong heritable factor in drug addiction: different gene expression levels can modulate the risk of developing a drug addiction and influence the transition from casual to compulsive drug abuse. However, epigenetics also plays an important role with epigenetic changes causing neuroplastic changes that influence the transition to drug addiction and drug-seeking behaviours, respectively.[Nilsson K et al., 2008]

• The methylation of BDNF gene promoters is linked to drug-seeking behaviours and substance abuse relapses.[Martinowich K et al, 2003],[Greenwald M et al, 2013]
• Chronic opiate abuse is associated with histone modifications that suppress BDNF gene expression in the ventral tegmental area causing behavioural adaptations.[Koo J et al., 2015]
• The progression from acute alcohol exposure to alcohol use disorder has been associated with an increase in histone acetylation of genes in the amygdala (e.g. BDNF and the neuropeptide Y gene, Npy). The negative anxiolytic effects of alcohol withdrawal correlate well with chromatin remodelling (i.e. the epigenome becomes condensed), resulting in alcohol dependence.
• Maintenance of a drug-addicted state has been causatively linked to the methylation of the BDNF promoter.[Xu X et al., 2016]

Furthermore, many studies have also shown that chronic drug abuse can perturb the chromatin structure and affect expression levels of some genes (i.e. FosB, Cdk5, and BDNF).[Biliński P et al.,  2012] 

These changes may have several influences on behaviour, including changing the behavioural response to a drug, initiating drug continuation and dependence, developing drug tolerance, or predisposing an individual to cycles of withdrawal and relapse.

Read more on the neurobiology of addiction. 

CONCLUSION

There is increasing evidence that epigenetics may play a role in the pathophysiology of psychiatric disorders such as major depressive disorder, psychosis and addiction.

Epigenetic changes occur in response to environmental changes but may also be heritable, which modify genetic expression directly and indirectly.

Epigenetic mechanisms such as histone modifications and DNA methylation at macro levels and promoter regions of key target proteins can produce long-lasting and stable gene expression changes.

Further delineation of epigenetic mechanisms that underlie psychiatric disorders may enhance our understanding of the pathogenesis of psychiatric disorders. They may allow the development of novel treatments that target these specific mechanisms.

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