Epigenetics
The term epigenetics was first coined in the 1940s by Conrad Waddington who described it as the division of biology that investigates the causative exchanges between genes and their upshots, which manifest the phenotype (Sidoli, Cheng & Jensen, 2012; Noble, 2015). Epigenetic modulation involves histone variants, post-translational modifications of amino acids on the amino-terminal tail of histone, and covalent modifications of DNA bases (Moore, 2015). Two forms of epigenetics exist namely molecular and molar, which are also termed as “bottom-up” and “top-down” epigenetics (Crews & Gore, 2014). Molecular epigenetics or epigenotypes revolve around the molecular level analysis while molar or epi phenotypes has its foundation on the rediscovery of Mendel’s research and involves evolution and adaptations as documented in psychobiology and evolutionary biology.
Epigenetics is also distinguished based on whether it is due to environmentally-induced epigenetic modifications or parental genomic imprinting (Lawson, Cheverud & Wolf, 2013). Parental genomic imprints are genes whose expression is based on origin, for example, maternal or paternal imprint. Environmentally induced epigenetic modifications and parental genomic imprint involve methylation and histone modification (Barlow & Bartolomei, 2014). The switching on and off of the imprinted genes is the same regardless of the parental origin. Tissues-specific imprints also exist though they show monoallelic expression of genes where only one allele of the gene is transcribed (Köhler, Wolff & Spillane, 2012).
Basic Principles of Epigenetics
There are approximately 23,000 genes in the genomic make-up of humans that are expressed in distinct cells at a given time (Venkatachalam, 2014). The expression of these genes by cells is managed through wrapping around groups (octamers) of globular histone proteins to form nucleosomes (Nestler, 2014). The nucleosomes are further organized into chromatins. Changes that occur in the chromatins determine the gene expression, which is the switching off of a gene (when the chromatin is condensed/silent) or switching it on when chromatin is in a relaxed state (Nestler, 2014). The dynamics of chromatin are enhanced by a controlled reversible mechanism of DNA methylation and histone modification. These two processes are enzyme based, with DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histones acetylases, histone methyltransferases and methyl-binding domain protein (MECP2) playing vital roles (Yedery & Jerse, 2015). Methylation of DNA involves the insertion of a methyl group to 5’-position of cytosine within CpG (cytosine/guanine) pairs. S-adenosylmethionine serves as the methyl donor.
The large number of 5’-methylcytosine in mammalian DNA is found in 5’-CpG-3’ dinucleotides. Methylation may also occur in non-CpG sequences, but at relative low frequencies (Nikolova, & Hariri, 2015). Histone proteins coordinate the organization of DNA and expression of genes. Histone-modifying enzymes ensure that a receptive DNA is either a candidate for silencing or transcription. Large numbers of acetylated histones and unmethylated DNA are found in the active sites of chromatin while methylated DNA and deacetylated histone proteins are found in the silent regions of chromatin (Meissner & Walter, 2013). DNA is normally tagged with a special epigenetics “tag” that confers a special quality for gene activation or silencing. These reversible modifications of DNA and histone proteins necessitate the expression of specific genes depending on precise developmental or biochemical signals such as hormonal levels, dietary constituents and drug exposure (Lucassen et al., 2013).
A critical Appraisal of Studying Genome-Wide DNA Methylation in Psychiatric Disorders
The Pros of Studying Genome-Wide DNA Methylation in Psychiatric Disorders
The biology of epigenetics has revolutionized every facet of medicine including psychiatry. Pridmore (2014) asserts that epigenetics has made more impact on psychiatry than on any other medical field. Genome-wide DNA methylation is the modern science used in the analysis of disease-associated methylation. DNA methylation is the key to several neurobiological and cognitive processes such as neurogenesis and brain development, neuronal activity, as well as learning and memory loss. Based on these observations, abnormal DNA methylation can be linked to psychiatric defects such as schizophrenia and bipolar disorder.
Genome-wide DNA methylation studies help in illuminating aberrant DNA methylation in psychiatric diseases. Various studies on epigenetic variation in psychiatric diseases have revealed methylated states of several genes. A study on rats to determine the features of mothering differences showed two traits that were passed to their offspring. Mothers with licking and grooming (LG) and arching back nursing (ABN) of pups produced mothers with the same qualities and vice versa. When the pups of low or high LG and ABN mothers were cross-fostered, the maternal qualities were inherited by the pups. The genome-wide DNA analysis revealed that there was a difference in DNA methylation of the glucocorticoid receptor (GR) gene promoter in the hippocampus (Roth, 2012). A similar study involving a suicide victim who had encountered abuse during childhood also showed discordance in glucocorticoid receptor (GR) gene promoter methylation. Genome-wide DNA analysis has been used to investigate the effects of depression, anxiety and SSRI medication from mother to child. Non, Binder, Kubzansky, and Michels (2014) show that there are significant changes in maternal CpG island when depression medication is used. Genome-wide DNA methylation analysis has enabled scientists to carry out global cross-association of psychiatric diseases. Melas et al. (2012) performed global DNA hypomethylation experiments to elucidate the global DNA hypomethylation in leukocytes of patients with schizophrenia. This study provided insight into the effects of commonly used SSRIs on DNA methylation.
The Cons of Studying Genome-Wide DNA Methylation in Psychiatric Disorders
Though epigenetics has improved the medical field, it has certain limitations. Most psychiatric diseases are heterogeneous syndromes with multiple causes, and their symptoms can only be inferred in human models (Wockner et al., 2014). A study by Guidotti et al. (2014) on the identification of epigenetic biomarkers of schizophrenia outlines that the study of biomarkers from the peripheral tissues such as leukocytes cannot be used to rule out some of the epigenetic signatures occurring in the brain. The epigenetic markers such of DNA methylation differ between leukocyte subtypes. In cases where there are difficulties using human specimens for studies, animal specimens can be used by first inducing the disorder in the animal (Januar, Saffery & Ryan, 2015).
Epigenetics of Schizophrenia
According to the epidemiological survey, schizophrenia is a psychiatric disorder that affects 1% of the population. There are no precise biomarkers that can be manipulated by clinicians to identify the disease. The ailment has a genetic risk of about 80%. Despite the high risks, studies on genes and polymorphisms associated with the disease account for little of these risks (Farrell et al., 2015). Environmental factors such as urbanity, child abuse, migrant status, use of hard drugs, maternal deficiency of vitamin D and prenatal infections also may contribute to schizophrenia. However, not all individuals exposed to these environmental factors develop the condition. Going by these observations, the interplay between the susceptibility genes and environmental factors is justifiable for the disease occurrence. Most studies of DNA methylation in association with schizophrenia are done on peripheral tissues as opposed to the brain because the peripheral tissues are readily available, and most biomarkers are common to both tissues (Wockner et al., 2014).
Various studies on the brain and peripheral tissues have attributed DNA methylation to schizophrenia. Some of the genes like HTR1A, HTR2A, BDNF, GRM2, GRM5 and COMT have differential methylation in schizophrenia (Teroganova, Girshkin, Suter, & Green, 2016). A DNA study of CpG island with schizophrenia patients shows significance differences in DNA methylation between patients and controls. Among the genes implicated in methylation are HTR1E, COMTD1 and SLC6A3, which were initially associated with schizophrenia (Nishioka et al., 2013). An investigation of monozygotic twins incongruous for schizophrenia also revealed differences in the methylation of several loci in peripheral blood. Several gene promoters such as HTR2A, COMT, SOX10 and RELN have also been studied for DNA methylation (Abdolmaleky, Shafa, Tsuang, & Thiagalingam, 2013).
Epigenetics of Bipolar Disorder
Bipolar disorder is an episodic sickness characterized by depression and periodic mood elevation. The etiopathology of bipolar disorder is linked to environmental factors that exert stress on brain function via epigenetic influence, particularly DNA methylation and histone proteins modifications (Schmitt, Malchow, Hasan, & Falkai, 2014). Studies have shown discrepancies in methylation of GPR24 and CTNNA2 genes, which are implicated in psychosis. Maternal and paternal methylation of X-allele has been implicated as the cause of discordance in BPD in twins. Studies of epigenetics of neurotransmission have attributed the hypermethylation of SLC6A4 gene in BPD lymphoblastoid cells of bipolar individuals at two CpG sites. The hypermethylation of SLC6A4 is correlated with SLC6A4 mRNA levels in individuals with S/S genotype of HTTLPR who have less expression suggesting that environmental factors play a partial role in the pathophysiology of BPD (Kang et al., 2013). Serotonin receptor subtype 1A (5HTR1A) found in the cortico-limbic regions of the brain has a high epigenetic alteration in BPD individuals leading to altered neurotransmitter binding (Teroganova et al., 2016). There is an increase in methylation of genes encoding 5HTR1A in the brain of a bipolar individual. Genome-wide studies have revealed important hypomethylation of CpG island of human leukocyte antigen 9 gene (HCG9) in bipolar patients. This gene is found on chromosome 6, which is associated with bipolar disorder (Kaminsky et al., 2012).
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