Epigenetic Alterations of Brain Non-Neuronal Cells in Major Mental Diseases

Abstract

The tissue-specific expression and epigenetic dysregulation of many genes in cells derived from the postmortem brains of patients have been reported to provide a fundamental biological framework for major mental diseases such as autism, schizophrenia, bipolar disorder, and major depression. However, until recently, the impact of non-neuronal brain cells, which arises due to cell-type-specific alterations, has not been adequately scrutinized; this is because of the absence of techniques that directly evaluate their functionality. With the emergence of single-cell technologies, such as RNA sequencing (RNA-seq) and other novel techniques, various studies have now started to uncover the cell-type-specific expression and DNA methylation regulation of many genes (e.g., TREM2, MECP2, SLC1A2, TGFB2, NTRK2, S100B, KCNJ10, and HMGB1, and several complement genes such as C1q, C3, C3R, and C4) in the non-neuronal brain cells involved in the pathogenesis of mental diseases. Additionally, several lines of experimental evidence indicate that inflammation and inflammation-induced oxidative stress, as well as many insidious/latent infectious elements including the gut microbiome, alter the expression status and the epigenetic landscapes of brain non-neuronal cells. Here, we present supporting evidence highlighting the importance of the contribution of the brain’s non-neuronal cells (in particular, microglia and different types of astrocytes) in the pathogenesis of mental diseases. Furthermore, we also address the potential impacts of the gut microbiome in the dysfunction of enteric and brain glia, as well as astrocytes, which, in turn, may affect neuronal functions in mental disorders. Finally, we present evidence that supports that microbiota transplantations from the affected individuals or mice provoke the corresponding disease-like behavior in the recipient mice, while specific bacterial species may have beneficial effects.

Epigenome Defines Aberrant Brain Laterality in Major Mental Illnesses

“…Epigenetic modifications are key contributors to cell differentiation for the establishment and maintenance of cells’ structural/functional diversity in multicellular organisms. This could be true for the epigenetic modifications of genes related to the structural/functional asymmetry of brain hemispheres, which are affected in SCZ and BD [ 99 , 100 , 101 ]. Like the genetic information, epigenetic information (called epigenetic memory) is also heritable [ 102 , 103 , 104 , 105 ].…”

“…Like the genetic information, epigenetic information (called epigenetic memory) is also heritable [ 102 , 103 , 104 , 105 ]. Nonetheless, they are influenced by diverse environmental factors such as malnutrition, infections, chemical contaminations, ecological conditions, and likely the social environment, as reviewed elsewhere [ 99 , 100 , 101 , 106 , 107 ]. For instance, a deficiency in methionine, choline, folic acid, and vitamin B12, which are essential for the functioning of the methylation machinery, as well as inflammation and oxidative stress induced by a pathological gut microbiome, can lead to epigenetic changes and the loss of epigenetic memory [ 99 , 100 , 101 , 108 , 109 , 110 ].…”

Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder

“…Interestingly, epigenetic influences may be responsible for accelerated biological aging of glial cells of patients with multiple sclerosis [175]. Finally, the potential impacts of the gut microbiome on the dysfunction of enteric and brain glia, as well as astrocytes, which, in turn, may affect neuronal functions in neurodevelopmental disorders including ASD should be considered [176] (Figure 2). In this regard, the impacts of gut microbiota disorders on the BBB and, indeed, on the pathology of ASD have been well documented [8,[177][178][179][180].…”

Epigenetic Aberrations in Major Psychiatric Diseases Related to Diet and Gut Microbiome Alterations

“…Instead, several hundred genetic mutations were found to be involved in the pathogenesis of any specific major mental disease, but the effect size of none of them reached even 1% [3,4]. Hence, it has been proposed that environmental factors through epigenetic alterations may play more significant roles in the pathogenesis of mental diseases [5,6]. Among various environmental factors such as toxins, contaminants, and malnutrition, the potential impacts of gut microbiota which affect and are affected by nutritional components have been under extensive scrutiny in recent years.…”