Rethinking the Epigenetic Framework to Unravel the Molecular Pathology of Schizophrenia.

Ariel Cariaga-Martinez,Raúl Alelú-Paz

doi:10.3390/ijms18040790

Abstract

Schizophrenia is a complex mental disorder whose causes are still far from being known. Although researchers have focused on genetic or environmental contributions to the disease, we still lack a scientific framework that joins molecular and clinical findings. Epigenetic can explain how environmental variables may affect gene expression without modifying the DNA sequence. In fact, neuroepigenomics represents an effort to unify the research available on the molecular pathology of mental diseases, which has been carried out through several approaches ranging from interrogating single DNA methylation events and hydroxymethylation patterns, to epigenome-wide association studies, as well as studying post-translational modifications of histones, or nucleosomal positioning. The high dependence on tissues with epigenetic marks compels scientists to refine their sampling procedures, and in this review, we will focus on findings obtained from brain tissue. Despite our efforts, we still need to refine our hypothesis generation process to obtain real knowledge from a neuroepigenomic framework, to avoid the creation of more noise on this innovative point of view; this may help us to definitively unravel the molecular pathology of severe mental illnesses, such as schizophrenia.

Highlights

Schizophrenia is a complex disease characterized by the heterogeneous presence of cognitive symptoms affecting perception, thought, attention, memory and emotion
Epigenetics represents a rapidly growing and promising field that is expected to lead to the unravelling of the molecular mechanisms that are characteristic of schizophrenia
The complex picture presented in this paper reflects the important contradictions that we find when we face the study of such a complex disease

Summary

Introduction

Schizophrenia is a complex disease characterized by the heterogeneous presence of cognitive symptoms affecting perception, thought, attention, memory and emotion. In contrast with cancer, where cell homogeneity is relatively constant ( not absolutely [10]), the neurons and brain share, in the words of Santiago Ramón y Cajal, a form-function combination that is hardly adaptable to the GWAS hypotheses Contributing to this disordered situation, Evrony et al, using single-cell DNA sequencing, demonstrated the existence of somatic mutations in different neurons; this means that, even inside a single brain, the genetic background is highly variable, so sampling methods must be extremely refined in order to get reproducible results [11]. These environmental contributions have been difficult to assess through molecular biology techniques For overcoming this issue, researchers are focusing on epigenetics, biological mechanisms that allow gene regulation without making changes to the DNA sequence. We will collect and summarize the current efforts to understand the molecular pathology of schizophrenia, through three main experimental approaches: (a) DNA methylation in brain samples (mainly assessed by Epigenome-Wide Association Studies or EWAS) and other DNA chemical modifications; (b) histone post-translational modifications; and (c) findings on the role of nucleosome remodeling in schizophrenia

DNA Methylation

DNA Hydroxymethylation

Histone Modifications

Nucleosome Remodeling

Findings

Conclusions