Epigenetic regulation in psychiatric disorders

Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.     

Differential regulation of DNA methylation in rat testis and its regulation by gonadotropic hormones

Eukaryotic DNA methylation occurs exclusively at the 5'-position of cytosine and has been implicated in the regulation of gene expression. Using high-performance liquid chromatography, the methylation of testis DNA during its development, in different cell populations and during regulation by gonadotropic hormones, were studied. The 5-mC content of testis DNA increased significantly from days 30 to days 150, while in 2-yr-old testis 5-mC content decreased significantly. Among various populations of testicular cells, pachytene spermatocyte DNA contained a significantly high amount of 5-mC when compared to spermatogonia, spermatids and mature sperm DNA. However, the 5-mC content of elongated spermatids was significantly less when compared to the above four fractions. Administration of follicle stimulating hormone to immature rats caused hypomethylation of seminiferous tubular DNA while luteinizing hormone caused similar effects in Leydig cells. These results indicate that in testis, DNA methylation is differentially regulated during development and is controlled by gonadotropic hormones.     

Functional characterization of zinc-finger motif in redox regulation of RPA-ssDNA interaction

The 70-kDa subunit of eukaryotic replication protein A (RPA) contains a conserved four cysteine-type zinc-finger motif that has been implicated in regulation of DNA replication and repair. Unlike other zinc-finger proteins, RPA zinc-finger motif is not a DNA-binding component, and deletion of the zinc-finger had very little effect on its ssDNA binding activity. Recently, we described a novel function for the zinc-finger motif in regulation of RPA's ssDNA binding activity through reduction-oxidation (redox). In this study, we carried out a detailed analysis of wild-type RPA and zinc-finger mutants in redox regulation of their ssDNA binding activity. Any mutation at a zinc-finger cysteine abolished its redox role in regulation of RPA-ssDNA interaction, suggesting that all four zinc-finger cysteines are required for redox regulation. Reactivity of cysteine residues to 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) indicated that wild-type RPA contained 8.2 reactive thiols/molecule including all four cysteines in the zinc-finger motif. Zinc-finger cysteines slowly reacted to DTNB as compared to others. Zn(II) was not only essential but also uniquely qualified for redox regulation of RPA-ssDNA interaction, suggesting that Zn(II)-cysteine coordination is crucial for the zinc-finger function. Redox status significantly affected initial interaction of RPA with ssDNA but had no effect after RPA formed a stable complex with DNA. Together, our results suggest that the zinc-finger motif mediates the transition of RPA-ssDNA interaction to a stable RPA-ssDNA complex in a redox-dependent manner.     

Circadian proteins in the regulation of cell cycle and genotoxic stress responses

The mammalian circadian system has been implicated in the regulation of the genotoxic stress response of an organism; however, the underlying molecular mechanisms are not well understood. Recent data suggest that, in addition to circadian variations in the expression of genes involved in genotoxic stress responses, core circadian proteins PERIOD1 (PER1) and TIMELESS (TIM) interact with components of the cell cycle checkpoint system, such as ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) and ataxia telangiectasia and Rad3-related (ATR)-Chk1, and are necessary for activation of Chk1 and Chk2 by DNA damage. Moreover, in complex with its recently identified partner, TIM-interacting protein (TIPIN), TIM interacts with components of the DNA replication system to regulate DNA replication processes under both normal and stress conditions. These discoveries shed new light on the role of core circadian proteins in various cellular and physiological processes.     

Epigenetics and cell cycle regulation in cystogenesis

The role of genetic mutations in the development of polycystic kidney disease (PKD), such as alterations in PKD1 and PKD2 genes in autosomal dominant PKD (ADPKD), is well understood. However, the significance of epigenetic mechanisms in the progression of PKD remains unclear and is increasingly being investigated. The term of epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. Epigenetic information can be inherited during mammalian cell division to sustain phenotype specifically and physiologically responsive gene expression in the progeny cells. A multitude of functional studies of epigenetic modifiers and systematic genome-wide mapping of epigenetic marks reveal the importance of epigenomic mechanisms, including DNA methylation, histone/chromatin modifications and non-coding RNAs, in PKD pathologies. Deregulated proliferation is a characteristic feature of cystic renal epithelial cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cyst formation and progression. Recent evidence suggests that alterations of DNA methylation and histone modifications on specific genes and the whole genome involved in cell cycle regulation and contribute to the pathogenesis of PKD. This review summarizes the recent advances of epigenetic mechanisms in PKD, which helps us to define the term of “PKD epigenetics” and group PKD epigenetic changes in three categories. In particularly, this review focuses on the interplay of epigenetic mechanisms with cell cycle regulation during normal cell cycle progression and cystic cell proliferation, and discusses the potential to detect and quantify DNA methylation from body fluids as diagnostic/prognostic biomarkers. Collectively, this review provides concepts and examples of epigenetics in cell cycle regulation to reveal a broad view of different aspects of epigenetics in biology and PKD, which may facilitate to identify possible novel therapeutic intervention points and to explore epigenetic biomarkers in PKD.     

Chromatin regulation and non-coding RNAs at mammalian telomeres

In eukaryotes, terminal chromosome repeats are bound by a specialized nucleoprotein complex that controls telomere length and protects chromosome ends from DNA repair and degradation. In mammals the “shelterin” complex mediates these central functions at telomeres. In the recent years it has become evident that also the heterochromatic structure of mammalian telomeres is implicated in telomere length regulation. Impaired telomeric chromatin compaction results in a loss of telomere length control. Progressive telomere shortening affects chromatin compaction at telomeric and subtelomeric repeats and activates alternative telomere maintenance mechanisms. Dynamics of chromatin structure of telomeres during early mammalian development and nuclear reprogramming further indicates a central role of telomeric heterochromatin in organismal development. In addition, the recent discovery that telomeres are transcribed, giving rise to UUAGGG-repeat containing TelRNAs/TERRA, opens a new level of chromatin regulation at telomeres. Understanding the links between the epigenetic status of telomeres, TERRA/TelRNA and telomere homeostasis will open new avenues for our understanding of organismal development, cancer and ageing.     

The role of protein kinase CK2 in the regulation of the insulin production of pancreatic islets

An appropriate regulation of the insulin production and secretion in pancreatic β-cells is necessary for the control of blood glucose homeostasis. The pancreatic duodenal homeobox factor-1 (Pdx-1) is among the various factors and signals which are implicated in the regulation of the insulin synthesis and secretion in the pancreatic β-cells. Recently, we identified Pdx-1 as a substrate for protein kinase CK2. Since CK2 is implicated in the regulation of many different cellular signaling pathways we now asked whether it might also be involved in the regulation of the insulin regulation in β-cells. Here, we show that insulin treatment of β-cells resulted in an elevated CK2 kinase activity. On the other hand down-regulation of CK2 activity by quinalizarin led to an elevated level of insulin. These results demonstrate that CK2 is implicated in the insulin regulation on pancreatic β-cells.     

Telomerase regulation

The intimate connection between telomerase regulation and human disease is now well established. The molecular basis for telomerase regulation is highly complex and entails multiple layers of control. While the major target of enzyme regulation is the catalytic subunit TERT, the RNA subunit of telomerase is also implicated in telomerase control. In addition, alterations in gene dosage and alternative isoforms of core telomerase components have been described. Finally, telomerase localization, recruitment to the telomere and enzymology at the chromosome terminus are all subject to modulation. In this review we summarize recent advances in understanding fundamental mechanisms of telomerase regulation.     

Gene regulation in response to DNA damage

To deal with different kinds of DNA damages, there are a number of repair pathways that must be carefully orchestrated to guarantee genomic stability. Many proteins that play a role in DNA repair are involved in multiple pathways and need to be tightly regulated to conduct the functions required for efficient repair of different DNA damage types, such as double strand breaks or DNA crosslinks caused by radiation or genotoxins. While most of the factors involved in DNA repair are conserved throughout the different kingdoms, recent results have shown that the regulation of their expression is variable between different organisms. In the following paper, we give an overview of what is currently known about regulating factors and gene expression in response to DNA damage and put this knowledge in context with the different DNA repair pathways in plants. This article is part of a Special Issue entitled: Plant gene regulation in response to abiotic stress.     

Hippocampal regulation of aversive memories

For many years, the hippocampal formation has been implicated in the regulation of negative emotion, yet the nature of this link has remained elusive. Recent studies have made important links between the hippocampus and regulation of stress hormones that affect aversive memory. Additional studies have shown that the hippocampus regulates the gating of fear by contextual information. An emerging literature also links the hippocampus to prediction errors during fear learning and extinction. The mechanisms by which the hippocampus regulates negative emotion are clearly complicated, but suggest that interventions aimed at restoring normal hippocampal function may help with disorders of negative affect, such as depression or post-traumatic stress disorder and depression.     

Glucocorticoid regulation of astrocytic fate and function

Glial loss in the hippocampus has been suggested as a factor in the pathogenesis of stress-related brain disorders that are characterized by dysregulated glucocorticoid (GC) secretion. However, little is known about the regulation of astrocytic fate by GC. Here, we show that astrocytes derived from the rat hippocampus undergo growth inhibition and display moderate activation of caspase 3 after exposure to GC. Importantly, the latter event, observed both in situ and in primary astrocytic cultures is not followed by either early- or late-stage apoptosis, as monitored by stage I or stage II DNA fragmentation. Thus, unlike hippocampal granule neurons, astrocytes are resistant to GC-induced apoptosis; this resistance is due to lower production of reactive oxygen species (ROS) and a greater buffering capacity against the cytotoxic actions of ROS. We also show that GC influence hippocampal cell fate by inducing the expression of astrocyte-derived growth factors implicated in the control of neural precursor cell proliferation. Together, our results suggest that GC instigate a hitherto unknown dialog between astrocytes and neural progenitors, adding a new facet to understanding how GC influence the cytoarchitecture of the hippocampus.     

Redox signaling in central neural regulation of cardiovascular function

One of the most prominent concepts to emerge in cardiovascular research over the past decade, especially in areas focused on angiotensin II (AngII), is that reactive oxygen species (ROS) are critical signaling molecules in a wide range of cellular processes. Many of the physiological effects of AngII are mediated by ROS, and alterations in AngII-mediated redox mechanisms are implicated in cardiovascular diseases such as hypertension and atherosclerosis. Although most investigations to date have focused on the vasculature as a key player, the nervous system has recently begun to gain attention in this field. Accumulating evidence suggests that ROS have important effects on central neural mechanisms involved in blood pressure regulation, volume homeostasis, and autonomic function, particularly those that involve AngII signaling. Furthermore, oxidant stress in the central nervous system is implicated in the neuro-dysregulation associated with some forms of hypertension and heart failure. The main objective of this review is to discuss the recent progress and prospects for this new field of central redox signaling in cardiovascular regulation, while also addressing the molecular tools that have spurred it forward.