Chapter 13 - 5-Methylcytosine and 5-hydroxymethylcytosine in psychiatric epigenetics

Abstract

Individuals with psychosis, including schizophrenia (SZ) and bipolar disorder patients (BP) with psychosis (BP+), express a complex symptomatology characterized by core symptoms that include positive and negative symptoms, as well as cognitive impairment. Autism spectrum disorders (ASD) are characterized by impaired social interactions, altered verbal and non-verbal communications, and repetitive or stereotyped behaviors. Although each disorder has a unique morbidity, age of onset, temporal progression, and responsiveness to pharmacological therapy, there are some shared features with respect to symptomatology that suggest common or overlapping endophenotypes. Postmortem studies of human SZ and BP+ brains indicate that there are considerable alterations in the transcriptome of a variety of cortical and limbic structures which, in turn, likely reflect widespread changes in the epigenome. mRNA profiling studies show expression levels that are both up- and/or downregulated in inhibitory GABAergic interneurons, excitatory (glutamatergic) pyramidal neurons, and glia at distinct stages of adolescent maturation and in the adult compared with non-psychiatric subjects (NPS). Alterations in the transcriptome and the epigenome have also been demonstrated in multiple types of neurons and brain regions in ASD, as well as in psychosis. Major depressive disorder (MDD) and suicide completers may also exhibit distinct and overlapping alterations in the epigenome. Many of the symptomatic phenotypes associated with these complex psychiatric disorders are likely the consequence of early-life stressors that occur during prenatal or early-life neurodevelopment. The establishment and maintenance of DNA methylation are essential during central nervous system maturation and neuronal differentiation. We propose that these DNA modifications represent interconvertible epigenetic states that are context dependent and likely associated with early developmental stress. Whereas CpG methylation is linked with transcriptional downregulation, the role of hydroxymethylation in transcriptional regulation is less clear although it is most often associated with transcriptional activation and RNA splice site selection. Studies also show that CpG binding by methyl-CpG-binding domain proteins acts to both facilitate and antagonize repressed chromatin. DNA-modifying proteins, such as DNMT1 and TET1, also bind CpGs independent of their catalytic function. In addition, both DNMT1 and MeCP2 are more abundant in GABAergic cortical neurons and hippocampal neurons, suggesting the possibility that inhibitory interneurons may differ in how they regulate gene expression as compared with excitatory neurons. Recent experimental observations raise the possibility that neuron-specific targets may be differentially exploited for pharmacological intervention in treating selective endophenotypes associated with psychiatric disorders. There is also widespread interest in understanding whether genome-wide methylation (methylomic) biomarkers present in blood might be useful in predicting BP+, SZ, BP, MDD, ASD, suicide, and responsiveness to specific psychiatric medications.