Epigenetics: DNA Methylation
Epigenome biomarkers
a. DNA methylation
In the broad sense, epigenetics can be seen as a bridge between the genotype and phenotype, where the final outcomes of a locus or a chromosome can be changed without altering the underlying DNA sequence (Goldberg et al. 2007), while epigenomics aims to study the location and nature of the gemonic sequences that are epigenetically modified (Fazzari and Greally 2004). Usually, three mechanisms have been attributed for epigenetics – DNA methylation, histone modification and noncoding RNA.
The key problem in molecular psychiatry is the difficulty of procuring brain tissue and one way to circumvent this issue by studying the epigenetic signatures measured in more accessible tissues such as blood as a …show more content…
surrogate marker for the brain. In a study that investigated the blood-brain correspondence of DNA methylation in schizophrenia found only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue. It also indicated that although most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status, a subset of peripheral data may proxy methylation status of brain tissue (Walton et al. 2016). But in an another methylome-wide association studies (MWAS), of the CpG-SNPs methylated in brain, 94% were also methylated in blood and justified replicating findings from blood in brain tissue (van den Oord et al. 2016).
Early life adversities increase the risk of psychosis in the future but the underlying mechanisms are unknown but epigenetic mechanisms could be a possible candidate. In an animal model of schizophrenia, prenatal bisphenol A (BPA) induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice. Similar changes are seen in the cord blood of humans exposed to high maternal BPA levels in utero suggesting BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation (Kundakovic et al. 2015).
A recent study tried to identify the blood biomarker signatures of environmental insults in individuals with schizophrenia using methylome-wide association study (MWAS). The top MWAS finding was in FAM63B, replicated with P = 2.3 × 10-10. It was identified that this part corresponds to the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Similarly, other top MWAS results were linked to hypoxia and, to a lesser extent, infection suggesting that prenatal and perinatal insults in schizophrenia could be identified by methylation in peripheral cells (Aberg et al. 2014). In a similar study, first episode psychosis individuals with childhood trauma had significantly lower LINE-1 methylation in comparison with individuals with first episode psychosis without childhood trauma suggesting childhood adversities might be associated with global DNA hypomethylation (Misiak et al. 2015).
When the global methylation pattern was studied in individuals with schizophrenia, results revealed a highly significant hypomethylation in patients with schizophrenia (P) methylation (P=0.001), and early onset was associated with lower methylation (P=0.002). The results suggest that there is a dysregulation of epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly reversed by antipsychotic medication (Melas et al. 2012). Another similar study found a significantly higher level of methylation at BDNF promoter I in individuals with schizophrenia compared to controls but the difference was small (Ikegame et al. 2013). Another study observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in individuals with schizophrenia suggesting the role of endocannabinoid system in psychosis. The results also suggest the potential of CNR1 DNA methylation levels in PBMCs as a biomarker for schizophrenia (D’Addario et al. 2017).
b. Histone modification
Many studies have noted that histones seen to be particularly dysregulated in schizophrenia. Few studies have explored the role of histone modification in peripheral lymphocytes in schizophrenia and indicated an abnormal increase in heterochromatin, likely due to increased H3K9 methylation and reduced H3K9 acetylation, both modifications associated with an increase in heterochromatin (Kosower et al. 1995, Gavin et al. 2009, Chase et al. 2013). Similarly, three histone modifications namely, G9a, GLP, and SETDB1, were found to be responsible for the majority of H3K9me modifications across the genome and are increased in lymphocytes from individuals with schizophrenia; notably, SETDB1 is the only HMT that specifically functions to di- and tri-methylate H3K9 (Wang et al. 2003, Zee et al. 2010).
c. MicroRNA
MicroRNA (miRNA) as a part of epigenetic mechanism, plays an important role in the gene expression and regulation. The use of miRNA as biomarkers is rapidly expanding in various medical disciplines especially cancer diagnosis and treatment. The role of miRNA as biomarkers and mechanism of pathogenesis is currently being explored in psychiatric disorders such as schizophrenia, bipolar and autism.
Dysregulation of miRNAs in the brain and peripheral blood mononuclear cells (PBMNCs) is well documented in individuals with schizophrenia and it is suggested that the changes in the miRNAs in the PBMNCs replicate the changes in the brain.
This has potentiated the importance of peripheral immune cells in miRNA research in schizophrenia. In a recent study, it was observed that early growth response protein 1 (EGR1) and miR-30a-5p were remarkably downregulated and neurogenic differentiation factor 1 (NEUROD1) was significantly upregulated in PBMNCs in individuals with acute psychosis. Also, with the initiation of antipsychotic medications, reversal of the phenomenon was observed, indicating the possible use of them as biomarkers. Similarly, Serum miR-21 found to decrease significantly with antipsychotic medications and this change was negatively correlated with improvement of positive, general psychopathology, and aggressiveness symptoms. This study showed the possible role of miRNAs in treatment response in individuals with schizophrenia. In another study, it was found that miR-94 from peripheral immune cells distinguished individuals who progressed and not progressed from high risk state to acute psychosis and suggesting the use of immune cell based miRNAs for assessing high risk states. In a study, global plasma miRNAs were profiled in a test cohort of 164 schizophrenia patients and 187 control subjects. The screening revealed the up-regulation of miR-130b and miR-193a-3p in individuals with schizophrenia but not in control subjects. Another similar study identified miR-132 as a potential and superior biomarker in peripheral blood that will allow discrimination of individuals with schizophrenia from normal
controls.
In another study, plasma miRNAs in individuals were analyzed and correlated with the symptomatology, treatment outcome and prognosis. The results identified miR-132, miR-181b, miR-30e and miR-432 as potential markers for symptomatology improvements, treatment responses and prognosis for individulas with schizophrenia. In a review, examining the serum samples of 115 patients suffering from schizophrenia and 40 healthy individuals, suggested that the miR-181b, miR-219-2-3p, miR-346, miR-195, miR-1308, miR-92a, miR-17, miR-103 and let-7g are the key players to reflect the schizophrenia illnesses status and may serve as candidate biomarkers for diagnosis of schizophrenia. A similar study found significantly increased expressions of miR-132, miR-195, miR-30e and miR-7 in plasma samples and miR-212, miR-34a and miR-30e in PBMNCs samples in individuals with schizophrenia when compared with normal controls while another study identified seven-miRNA signature (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) and found to be differentially correlated with negative symptoms, cognitive performance scores and event-related potentials.
Interestingly, a study which examined the relationship between cancer incidence and schizophrenia found that let-7, miR-98 and miR-183 may play an important oncosuppressive role through their regulatory impact in gene expression irrespective of the presence of schizophrenia and possible role of these and other micro-RNAs in the molecular pathways of schizophrenia. This highlighted the role of miRNAs as a protective biomarker for cancer in schizophrenia.
As these studies suggest, there are multiple miRNAs are implicated in the pathogenesis of schizophrenia and the biomarker potential of these miRNAs are currently explored.
a. DNA methylation
In the broad sense, epigenetics can be seen as a bridge between the genotype and phenotype, where the final outcomes of a locus or a chromosome can be changed without altering the underlying DNA sequence (Goldberg et al. 2007), while epigenomics aims to study the location and nature of the gemonic sequences that are epigenetically modified (Fazzari and Greally 2004). Usually, three mechanisms have been attributed for epigenetics – DNA methylation, histone modification and noncoding RNA.
The key problem in molecular psychiatry is the difficulty of procuring brain tissue and one way to circumvent this issue by studying the epigenetic signatures measured in more accessible tissues such as blood as a …show more content…
surrogate marker for the brain. In a study that investigated the blood-brain correspondence of DNA methylation in schizophrenia found only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue. It also indicated that although most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status, a subset of peripheral data may proxy methylation status of brain tissue (Walton et al. 2016). But in an another methylome-wide association studies (MWAS), of the CpG-SNPs methylated in brain, 94% were also methylated in blood and justified replicating findings from blood in brain tissue (van den Oord et al. 2016).
Early life adversities increase the risk of psychosis in the future but the underlying mechanisms are unknown but epigenetic mechanisms could be a possible candidate. In an animal model of schizophrenia, prenatal bisphenol A (BPA) induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice. Similar changes are seen in the cord blood of humans exposed to high maternal BPA levels in utero suggesting BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation (Kundakovic et al. 2015).
A recent study tried to identify the blood biomarker signatures of environmental insults in individuals with schizophrenia using methylome-wide association study (MWAS). The top MWAS finding was in FAM63B, replicated with P = 2.3 × 10-10. It was identified that this part corresponds to the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Similarly, other top MWAS results were linked to hypoxia and, to a lesser extent, infection suggesting that prenatal and perinatal insults in schizophrenia could be identified by methylation in peripheral cells (Aberg et al. 2014). In a similar study, first episode psychosis individuals with childhood trauma had significantly lower LINE-1 methylation in comparison with individuals with first episode psychosis without childhood trauma suggesting childhood adversities might be associated with global DNA hypomethylation (Misiak et al. 2015).
When the global methylation pattern was studied in individuals with schizophrenia, results revealed a highly significant hypomethylation in patients with schizophrenia (P) methylation (P=0.001), and early onset was associated with lower methylation (P=0.002). The results suggest that there is a dysregulation of epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly reversed by antipsychotic medication (Melas et al. 2012). Another similar study found a significantly higher level of methylation at BDNF promoter I in individuals with schizophrenia compared to controls but the difference was small (Ikegame et al. 2013). Another study observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in individuals with schizophrenia suggesting the role of endocannabinoid system in psychosis. The results also suggest the potential of CNR1 DNA methylation levels in PBMCs as a biomarker for schizophrenia (D’Addario et al. 2017).
b. Histone modification
Many studies have noted that histones seen to be particularly dysregulated in schizophrenia. Few studies have explored the role of histone modification in peripheral lymphocytes in schizophrenia and indicated an abnormal increase in heterochromatin, likely due to increased H3K9 methylation and reduced H3K9 acetylation, both modifications associated with an increase in heterochromatin (Kosower et al. 1995, Gavin et al. 2009, Chase et al. 2013). Similarly, three histone modifications namely, G9a, GLP, and SETDB1, were found to be responsible for the majority of H3K9me modifications across the genome and are increased in lymphocytes from individuals with schizophrenia; notably, SETDB1 is the only HMT that specifically functions to di- and tri-methylate H3K9 (Wang et al. 2003, Zee et al. 2010).
c. MicroRNA
MicroRNA (miRNA) as a part of epigenetic mechanism, plays an important role in the gene expression and regulation. The use of miRNA as biomarkers is rapidly expanding in various medical disciplines especially cancer diagnosis and treatment. The role of miRNA as biomarkers and mechanism of pathogenesis is currently being explored in psychiatric disorders such as schizophrenia, bipolar and autism.
Dysregulation of miRNAs in the brain and peripheral blood mononuclear cells (PBMNCs) is well documented in individuals with schizophrenia and it is suggested that the changes in the miRNAs in the PBMNCs replicate the changes in the brain.
This has potentiated the importance of peripheral immune cells in miRNA research in schizophrenia. In a recent study, it was observed that early growth response protein 1 (EGR1) and miR-30a-5p were remarkably downregulated and neurogenic differentiation factor 1 (NEUROD1) was significantly upregulated in PBMNCs in individuals with acute psychosis. Also, with the initiation of antipsychotic medications, reversal of the phenomenon was observed, indicating the possible use of them as biomarkers. Similarly, Serum miR-21 found to decrease significantly with antipsychotic medications and this change was negatively correlated with improvement of positive, general psychopathology, and aggressiveness symptoms. This study showed the possible role of miRNAs in treatment response in individuals with schizophrenia. In another study, it was found that miR-94 from peripheral immune cells distinguished individuals who progressed and not progressed from high risk state to acute psychosis and suggesting the use of immune cell based miRNAs for assessing high risk states. In a study, global plasma miRNAs were profiled in a test cohort of 164 schizophrenia patients and 187 control subjects. The screening revealed the up-regulation of miR-130b and miR-193a-3p in individuals with schizophrenia but not in control subjects. Another similar study identified miR-132 as a potential and superior biomarker in peripheral blood that will allow discrimination of individuals with schizophrenia from normal
controls.
In another study, plasma miRNAs in individuals were analyzed and correlated with the symptomatology, treatment outcome and prognosis. The results identified miR-132, miR-181b, miR-30e and miR-432 as potential markers for symptomatology improvements, treatment responses and prognosis for individulas with schizophrenia. In a review, examining the serum samples of 115 patients suffering from schizophrenia and 40 healthy individuals, suggested that the miR-181b, miR-219-2-3p, miR-346, miR-195, miR-1308, miR-92a, miR-17, miR-103 and let-7g are the key players to reflect the schizophrenia illnesses status and may serve as candidate biomarkers for diagnosis of schizophrenia. A similar study found significantly increased expressions of miR-132, miR-195, miR-30e and miR-7 in plasma samples and miR-212, miR-34a and miR-30e in PBMNCs samples in individuals with schizophrenia when compared with normal controls while another study identified seven-miRNA signature (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) and found to be differentially correlated with negative symptoms, cognitive performance scores and event-related potentials.
Interestingly, a study which examined the relationship between cancer incidence and schizophrenia found that let-7, miR-98 and miR-183 may play an important oncosuppressive role through their regulatory impact in gene expression irrespective of the presence of schizophrenia and possible role of these and other micro-RNAs in the molecular pathways of schizophrenia. This highlighted the role of miRNAs as a protective biomarker for cancer in schizophrenia.
As these studies suggest, there are multiple miRNAs are implicated in the pathogenesis of schizophrenia and the biomarker potential of these miRNAs are currently explored.