Epigenetics mechanisms in schizophrenia

Schizophrenia is a psychiatric syndrome characterized by psychotic symptoms of hallucinations, delusions and disorganized speech, by negative symptoms such as decreased motivation and diminished expressiveness, and by cognitive deficits. There is wide variation in the ability of persons with schizophrenia to function in their daily lives, with some being severely disabled and others able to function at a high level (Marder 2019). Persons with schizophrenia have lower gray-matter volumes on magnetic resonance imaging than age-matched controls and fewer dendrites and dendritic spines in postmortem studies. These structural features are hypothesized to contribute to altered physiological activity and functional connectivity among the prefrontal cortex, temporal cortex, thalamus, hippocampus, and cerebellum (Marder 2019). There have been also reports of numerous biochemical changes in schizophrenia indicative of neurotransmitter dysfunction in multiple systems, among the most prominent being dopamine, glutamate, serotonin, and γ‎-aminobutyric acid (GABA) (Gill 2016).

The underlying causes of schizophrenia include environmental and genetic factors, pointing to a multifarious etiology. The prevailing explanation is based on the interplay between predisposing genes and environmental exposures (Smigielski et al., 2019). Heritable factors are estimated to explain 80% of the risk of schizophrenia in a population. However, only a small portion of this heritable component has been shown to be attributable to common disease associated single-nucleotide variants, or to larger but rare mutations.

Genome research has revealed that epigenetics is an additional layer of regulation of genes and gene-associated proteins (Smigielski et al., 2019). Epigenetics refers to the changes in gene function that are heritable but do not entail a change in DNA sequence (Dupont et al., 2009), and encompasses heritable alterations in chromatin function and structure. Epigenetic mechanisms also regulate important brain-related functions, such as neurogenesis, neurodegeneration, neuronal activity, and cognition (Smigielski et al., 2019).

Accumulated evidence suggests that epigenetic regulation of genome may mediate dynamic gene–environment interactions at the molecular level by modulating the expression of psychiatric phenotypes through transcription factors (Smigielski et al., 2019). The dynamic and interactive nature of epigenetics may thus contribute to the multi-level etiology of most psychiatric conditions (Smigielski et al., 2019). These characteristics of epigenetics raise the possibility that epigenetic defects may be corrected through different interventions including pharmacological treatments. (Swathy et al., 2017). In fact, several antipsychotics have been found to influence epigenetic signaling (Smigielski et al., 2019).

DNA methylation, post-translational histone modification, and RNA interference, particularly through micro- RNAs (miRNAs), are three epigenetic mechanisms.

DNA methylation, the most documented epigenetic mechanism, is a crucial regulator of gene expression and gene silencing, mainly by blocking the binding of transcription factors at gene promoters and by altering chromatin structure. At present, there are varying levels of evidence in schizophrenia for the altered DNA methylation status of genes regulating dopamine, serotonin, γ-aminobutyric acid, and neurotrophin availability, as well as for a few genes with less understood functions (Smigielski et al., 2019). Alelú-Paz et al. analyzed the epigenome in several brain regions from schizophrenic patients with severe cognitive impairment and found different DNA methylation signatures depending on the brain area analyzed (Alelú-Paz et al., 2016). Aberg et al. conducted a methylome-wide association study of schizophrenia identifying blood biomarker signatures of environmental insults. Their results demonstrated how methylation studies can yield biomarkers that can be used to potentially improve disease management (Aberg et al., 2015).

Histone modifications, referring to modifications to the proteins that package and order DNA into nucleosomes, may be transcriptionally permissive or repressive (Smigielski et al., 2019). To date, very little is known about the histone modifications in the context of schizophrenia. Several lines of evidence suggest that histone modifications in specific candidate genes may contribute to the pathogenesis of prefrontal dysfunction. (Swathy et al. 2017).

The third epigenetic category involves miRNAs, which are a kind of non-coding RNAs that engage in post-transcriptional repression or messenger RNA destabilization of many targeted genes. The existing data generally support the hypothesis that miRNA is dysregulated in schizophrenia and other psychotic disorders (Smigielski et al., 2019). It has been shown that the genetically based dysregulation of miRNAs undermines miRNA inhibitory effects, resulting in the abnormal upregulation of genome transcription contributing to the development of schizophrenia (Zhang et al., 2015).

The recent understandings in epigenetics on schizophrenia has provided deeper insights in identifying epigenetic patterns of histone modifications, methylations and miRNAs in the pathogenesis of the disease. Accumulative evidence suggests that antipsychotic drugs can also alter the epigenetic homeostasis. Thus, the emerging field of pharmacoepigenomics is providing promising insights into the role of drugs in modulating host epigenome, as well as in addressing interindividual variability in drug response and drug-related adverse effects (Swathy et al., 2017).

References

• Aberg KA, McClay JL, Nerella S, et al. Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults. JAMA Psychiatry, 2014;71(3):255–264.
• Alelú-Paz R, Carmona FJ, Sanchez-Mut JV, et al. Epigenetics in Schizophrenia: A Pilot Study of Global DNA Methylation in Different Brain Regions Associated with Higher Cognitive Functions. Front Psychol. 2016;7:1496.
• Gill K, Grace A. The role of neurotransmitters in schizophrenia. In: Schizophrenia and Psychotic Spectrum Disorders. Oxford University Press; 2016. p.153–84
• Stephen R. Marder and Tyrone D. Cannon. Schizophrenia. N Engl J Med. 2019 Oct 31;381(18):1753-1761.
• Montano C, Taub MA, Jaffe A, et al. Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study. JAMA Psychiatry, 2016;73(5):506–514.
• Smigielski L, Jagannath V, Rössler W, Walitza S, Grünblatt E. Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings. Mol Psychiatry. 2020 Jan 6 [Epub ahead of print].
  Swathy B, Banerjee M. Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy. Epigenomics, 2017;9(5):721–736.
• Zhang F, Xu Y, Shugart YY, et al. Converging evidence implicates the abnormal microRNA system in schizophrenia. Schizophr Bull.,2015;41(3):728–735.