Epigenetic and Schizophrenia

Schizophrenia is a complex psychiatric disorder characterised by the presence of positive, negative and cognitive symptoms that lack a unifying neuropathology. The absence of consistently replicated genetic effects, together with evidence for lasting changes in gene expression after environmental exposures, suggests a role of epigenetic mechanisms. In this chapter, we will focus on these mechanisms, such as DNA methylation, hydroxymethylation, histone modifications or non-coding RNA, as key mechanisms through which environmental factors interact with individual’s genetic constitution which affect the risk of psychotic conditions throughout life. Due to the advances experienced in recent years, it is to be expected that in the next decades, an increasing amount of data will provide us with a more complete landscape of the contribution of epigenetics to the development of mental disorders such as schizophrenia

Epigenetics in schizophrenia: a pilot study of global DNA methylation in different brain regions associated with higher cognitive functions

Attempts to discover genes that are involved in the pathogenesis of major psychiatric disorders have been frustrating and often fruitless. Concern is building about the need to understand the complex ways in which nature and nurture interact to produce mental illness. We analyze the epigenome in several brain regions from schizophrenic patients with severe cognitive impairment using high-resolution (450K) DNA methylation array. We identified 139 differentially methylated CpG sites included in known and novel candidate genes sequences as well as in and intergenic sequences which functions remain unknown. We found that altered DNA methylation is not restricted to a particular region, but includes others such as CpG shelves and gene bodies, indicating the presence of different DNA methylation signatures depending on the brain area analyzed. Our findings suggest that epimutations are not relatables between different tissues or even between tissues' regions, highlighting the need to adequately study brain samples to obtain reliable data concerning the epigenetics of schizophrenia

Epigenetics in schizophrenia: a pilot study of global DNA methylation in different brain regions associated with higher cognitive functions

Attempts to discover genes that are involved in the pathogenesis of major psychiatric disorders have been frustrating and often fruitless. Concern is building about the need to understand the complex ways in which nature and nurture interact to produce mental illness. We analyze the epigenome in several brain regions from schizophrenic patients with severe cognitive impairment using high-resolution (450K) DNA methylation array. We identified 139 differentially methylated CpG sites included in known and novel candidate genes sequences as well as in and intergenic sequences which functions remain unknown. We found that altered DNA methylation is not restricted to a particular region, but includes others such as CpG shelves and gene bodies, indicating the presence of different DNA methylation signatures depending on the brain area analyzed. Our findings suggest that epimutations are not relatables between different tissues or even between tissues' regions, highlighting the need to adequately study brain samples to obtain reliable data concerning the epigenetics of schizophrenia

Análisis estereológico de los núcleos mediodorsal y geniculado medial del tálamo en el cerebro humano normal y esquizofrénico

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina. Departamento de Anatomía, Histología y Neurociencia. Fecha de lectura: 19 de Diciembre del 200

Rethinking the Epigenetic Framework to Unravel the Molecular Pathology of Schizophrenia

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

Rethinking schizophrenia through the lens of evolution: shedding light on the enigma

Schizophrenia refers to a complex psychiatric illness characterized by the heterogenic presence of positive, negative and cognitive symptoms occurring in all human societies. The fact that the disorder lacks a unifying neuropathology, presents a decreased fecundity of the affected individuals and has a cross-culturally stable incidence rate, makes it necessary for an evolutionary explanation that fully accounts for the preservation of “schizophrenic genes” in the global human genepool, explaining the potential sex differences and the heterogeneous cognitive symptomatology of the disorder and is consistent with the neuropsychological, developmental and evolutionary findings regarding the human brain. Here we proposed a new evolutionary framework for schizophrenia that is consistent with findings presented in different dimensions, considering the disorder as a form of brain functioning that allows us to adapt to the environment and, ultimately, maintain the survival of the species. We focus on the epigenetic regulation of thalamic interneurons as a major player involved in the development of the clinical picture characteristic of schizophrenia

DNA Methylation, Histone Modifications, and Signal Transduction Pathways: A Close Relationship in Malignant Gliomas Pathophysiology

Gliomas are the most common type of primary brain tumor. Although tremendous progress has been achieved in the recent years in the diagnosis and treatment, its molecular etiology remains unknown. In this regard, epigenetics represents a new approach to study the mechanisms that control gene expression and function without changing the sequence of the genome. In the present paper we describe the main findings about the alterations of cell signaling pathways in the most aggressive glioma in the adult population, namely, glioblastoma, in which epigenetic mechanisms and the emerging role of cancer stem cell play a crucial function in the development of new biomarkers for its detection and prognosis and the corresponding development of new pharmacological strategies

The Vast Complexity of the Epigenetic Landscape during Neurodevelopment: An Open Frame to Understanding Brain Function

Development is a well-defined stage-to-stage process that allows the coordination and maintenance of the structure and function of cells and their progenitors, in a complete organism embedded in an environment that, in turn, will shape cellular responses to external stimuli. Epigenetic mechanisms comprise a group of process that regulate genetic expression without changing the DNA sequence, and they contribute to the necessary plasticity of individuals to face a constantly changing medium. These mechanisms act in conjunction with genetic pools and their correct interactions will be crucial to zygote formation, embryo development, and brain tissue organization. In this work, we will summarize the main findings related to DNA methylation and histone modifications in embryonic stem cells and throughout early development phases. Furthermore, we will critically outline some key observations on how epigenetic mechanisms influence the rest of the developmental process and how long its footprint is extended from fecundation to adulthood

Epigenetics in schizophrenia: a pilot study of global DNA methylation in different brain regions associated with higher cognitive functions.

Attempts to discover genes that are involved in the pathogenesis of major psychiatric disorders have been frustrating and often fruitless. Concern is building about the need to understand the complex ways in which nature and nurture interact to produce mental illness. We analyze the epigenome in several brain regions from schizophrenic patients with severe cognitive impairment using high-resolution (450k) DNA methylation array. We identified 159 differentially methylated CpG sites included in known and novel candidate genes sequences as well as in and intergenic sequences wich functions remain unknown. We found that altered DNA methylation is not restricted to a particular region, but includes others such as CpG shelves and gene bodies, indicating the presence of different DNA methylation signatures depending on the brain area analyzed. Our findings suggest that epimutations are not relatables between different tissues or even between tissues’ regions, highlighting the need to adqueately study brain samples to obtain reliable data concerning the epigenetics of schizophrenia