DNA methylation may underlie diverse neurodevelopmental disorders of genetic as well as environmental origins
This contribution was written by Dr. Christina A. Castellani and Dr. Shiva M. Singh with critical input from Benjamin I. Laufer (PhD Candidate) and Dr. Melkaye G Melka. Castellani is a Postdoctoral Fellow in the Institute of Genetic Medicine at the Johns Hopkins School of Medicine. The other authors are affiliated with The University of Western Ontario where Singh holds the role of Distinguished University Professor. The research discussed was performed in the Singh Lab in Ontario, Canada.
Neurodevelopmental disorders are complex in both their etiology and presentation. Theoretically, the disruption of neurodevelopment at distinct time points facilitated by epigenetic insults interacting with a patient’s genetic background may result in altered DNA methylation across a wide variety of disorders with neurodevelopmental origins. Psychosis is a symptom of mental illness characterized by hallucinations and/or delusions and is thought to result from neurodevelopmental insults. Classically, it is associated with schizophrenia, a complex disease that is known to cluster in some families. Also, there is accumulating evidence that schizophrenia may result in response to drugs and chemicals including cocaine and cannabis. It causes grave hardships to patients, families and society and is characterized by a highly heterogeneous presentation across cases. The majority of genetic research on psychosis has focused on individual diseases, such as schizophrenia. However, less attention has been given towards finding a common thread that may underlie mental disorders with and without psychosis.
We tackled the issue of the complexity of the presentation of psychosis and its relationship to DNA methylation in our article published in Epigenomics titled “DNA Methylation in Psychosis: Insights into Etiology and Treatment” (Castellani et al., 2015a). This perspective article was primarily based on the results of two independent experiments. The first assessed genome-wide methylation differences between monozygotic twins discordant for schizophrenia (Castellani et al., 2015b) and the other compared genome-wide methylation in an animal model (rat) in response to an antipsychotic drug (Olanzapine) used to treat psychosis (Melka et al., 2014). We found genome-wide DNA methylation changes in the blood DNA of the affected twins that were not present in the unaffected twins. It paralleled the differences in DNA methylation identified between rats treated with Olanzapine and their matched controls. Interestingly, the genes and pathways identified in the two unrelated experiments were not random. They specifically affect genes and pathways that are known to be involved in neurodevelopment and psychiatric disorders. Thus, we encourage researchers in this field to first consider the potential effect of medication use before arriving at conclusions regarding DNA methylation aberrations that are causative of disease.
Further, we hypothesize that DNA methylation may provide a mechanistic underpinning for the neurodevelopmental origin of most mental disorders. Through additional experiments performed in our lab, we add to the large body of evidence, that DNA methylation is also critical in Fetal Alcohol Spectrum Disorders (FASD), another group of neurodevelopmental disorders which are caused by maternal drinking during pregnancy. Specifically, we bring to light two sets of observations. The first deals with a mouse (C57BL/6J) model of FASD (Laufer et al., 2013). Here, a prenatal alcohol exposure is shown to cause long lasting changes in genome-wide DNA methylation in the adult brain of resulting pups. Once again, the genes affected are not random. They are involved in neurodevelopment and directly affect learning and memory (Kleiber et al., 2014). Additionally, the results suggest that there is no dose and time of pregnancy that is totally safe from alcohol exposure (Singh et al., 2014). The second set of results have attempted to replicate the mouse results on cheek swab DNA samples from ~6 yr old children with a confirmed diagnosis of FASD and their matched controls. In another article from our group published in Epigenomics entitled “Associative DNA Methylation Changes in Children with Prenatal Alcohol Exposure”, we report that FASD children have altered DNA methylation in their cheek swab DNA that is not found in controls (Laufer et al., 2015). Also, the genes affected in this human study are not random but are also directly involved in neurodevelopment. We have identified for the first time a list of genes that show altered DNA methylation in children with FASD as compared to matched controls (Laufer et al., 2015). However, we have also found that sex, medication, and age can alter DNA methylation profiles.
It is now well established that increased methylation in the promoter region of genes is associated with reduced expression. However, the difference in DNA methylation levels across mental health patients, its genetic or environmental causes, and its association with expression of psychosis relevant genes remains to be elucidated. The next challenge is to identify a specific set of genes that consistently shows altered methylation in patients born with complex mental diseases and yet are lacking in matched controls. This will be extremely challenging for two reasons: complex mental diseases are highly heterogeneous in both causes and consequences. For example, in the case of Fetal Alcohol Spectrum Disease, the most severe form is called Fetal Alcohol Syndrome, however milder presentations can produce a spectrum of symptoms. In this and many other heterogeneous diseases, no two patients are identical in symptomatology. In FASD, this heterogeneity may result from variable dose, timing and patterns of alcohol exposure during neurogenesis and/or synaptogenesis. Also, it may depend on the background genotype including familial and generational patterns of drinking. Of course, as researchers we strive to identify a specific set of common genes as biomarkers and in the case of epigenetics, this should manifest as genes whose methylation is increased or decreased in response to prenatal alcohol exposure leading to FASD through the aberration of neurodevelopment and subsequent mental functions.
In conclusion, DNA methylation is critical in the regulation of chromatin structure and gene expression, and plays a role in the etiology of a number of complex mental diseases. The study of the diseases in particular continues to provide novel insights into the role of DNA methylation and other epigenetic modifications in mental disorders. It has become apparent that these modifications are dynamic and are caused by both genetic and environmental factors. Here, we present examples to suggest that the manifestation of complex mental disease underlies DNA methylation. Further, the genes affected by methylation changes affect a number of shared pathways especially involving neurodevelopment and function (Castellani et al., 2015b, 2015c). Additional insight, however, must be sought to confirm this proposition in less heterogeneous subsets of tissue samples, as well as to examine the spatiotemporal role of DNA methylation across a number of complex mental diseases and disorders.
Castellani, C.A., Melka, M.G., Diehl, E.J., Laufer, B.I., O’Reilly, R.L., and Singh, S.M. (2015a). DNA methylation in psychosis: insights into etiology and treatment. Epigenomics 7, 67–74.
Castellani, C.A., Laufer, B.I., Melka, M.G., Diehl, E.J., O’Reilly, R.L., and Singh, S.M. (2015b). DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks. BMC Med. Genomics 8, 17.
Castellani, C.A., Melka, M.G., Gui, J.L., O’Reilly, R.L., and Singh, S.M. (2015c). Integration of DNA sequence and DNA methylation changes in monozygotic twin pairs discordant for schizophrenia. Schizophr. Res. 169, 433–440.
Kleiber, M.L., Diehl, E.J., Laufer, B.I., Mantha, K., Chokroborty-Hoque, A., Alberry, B., and Singh, S.M. (2014). Long-term genomic and epigenomic dysregulation as a consequence of prenatal alcohol exposure: a model for fetal alcohol spectrum disorders. Front. Genet. 5, 161.
Laufer, B.I., Mantha, K., Kleiber, M.L., Diehl, E.J., Addison, S.M.F., and Singh, S.M. (2013). Long-lasting alterations to DNA methylation and ncRNAs could underlie the effects of fetal alcohol exposure in mice. Dis. Model. Mech. 6, 977–992.
Laufer, B.I., Kapalanga, J., Castellani, C.A., Diehl, E.J., Yan, L., and Singh, S.M. (2015). Associative DNA methylation changes in children with prenatal alcohol exposure. Epigenomics 7, 1259–1274.
Melka, M.G., Laufer, B.I., McDonald, P., Castellani, C.A., Rajakumar, N., O’Reilly, R., and Singh, S.M. (2014). The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum. Clin. Epigenetics 6, 1.
Singh, S.M., Laufer, B.I., and Kapalanga, J. (2014). Fetal alcohol and the right to be born healthy…. Front. Genet. 5, 356.