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Special Issue "Epigenetics of Neurodevelopmental Disorders"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2018).

Special Issue Editor

Dr. Takeo Kubota

Guest Editor
Past Professor, Department of Epigenetic Medicine, University of Yamanashi, Yamanashi 409-3898, Japan Present affiliation, Supervising Doctor, Kofu Office, Yamanashi Prefecture Red Cross Blood Center, Japanese Red Cross Society, 1-6-1 Ikeda, Kofu-city, Yamanashi, 400-0062, Japan
Interests: neurodevelopmental disorder; epigenome; environmental stress; epigenetic reversibility; preemptive medicine
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Epigenetics is a gene regulation mechanism that does not depend on genomic DNA sequences, but depends instead on chemical modification of genomic DNA and histone proteins around which DNA is wrapped. The failure of epigenetic mechanisms is known to cause congenital neurodevelopmental disorders (NDDs), which include genomic imprinting disorders (e.g., Prader-Willi and Angelman syndrome), X-chromosome inactivation disorders (e.g., ring X Turner syndrome), and epigenetic regulation-associated molecule disorders (e.g., Rett and Kleefstra syndromes). These indicate that the epigenetic system is essential for normal neurodevelopment.
It has recently reported that the number of children with NDDs has increased in several countries, such as the US, Korea, and Japan, in which environmental factors, rather than genetic factors, are thought to be involved in this increase. Since epigenetic modifications in DNA are more vulnerable to environmental stress, such as malnutrition, environmental chemicals, and mental stress, than DNA sequence, especially during the early period of life, one can speculate that current socio-environmental factors cause acquired NDDs via epigenetic alterations in the brain.
The epigenome has a reversible property since it is based on removable residues on genomic DNA. Thus, environmentally induced epigenomic alterations can be potentially restored. In fact, some medicines for psychiatric and epileptic diseases are known to restore an altered epigenome, resulting in the correction of gene expression. Therefore, epigenomic-based preemptive medicine that consists of early detection using epigenomic signatures and early intervention that take advantages of the use of epigenomic reversibility are expected.
In this context, I would like to invite review and original articles that focus on epigenetic understanding of brain function, brain development, and NDDs. Additionally, articles associated with epigenome–environmental factor interaction in the brain are desired in this Special Issue.

Dr. Takeo Kubota
Guest Editor

Manuscript Submission Information

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Keywords

  • epigenetics
  • neurodevelopmental disorders
  • genomic imprinting
  • X-chromosome inactivation
  • congenital
  • acquired
  • epigenomic signatures
  • early intervention
  • preemptive medicine
  • epigenome–environmental factor interaction

Published Papers (9 papers)

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Editorial

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Open AccessEditorial
Epigenetics of Neurodevelopmental Disorders Comes of Age with Roles in Clinical and Educational Applications
Int. J. Mol. Sci. 2018, 19(9), 2720; https://doi.org/10.3390/ijms19092720 - 12 Sep 2018
Cited by 1
Abstract
Epigenetics is a gene regulation mechanism that does not depend on genomic DNA sequences, but depends instead on chemical modifications of DNA and histone proteins. [...] Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)

Research

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Open AccessArticle
MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury
Int. J. Mol. Sci. 2017, 18(7), 1356; https://doi.org/10.3390/ijms18071356 - 24 Jun 2017
Cited by 31
Abstract
Cerebral edema, primarily caused by disruption of the blood-brain barrier (BBB), is one of the serious complications associated with brain injury in neonatal hypoxic-ischemic encephalopathy (HIE). Our recent study demonstrated that the hypoxic-ischemic (HI) treatment significantly increased microRNA-210 (miR-210) in the neonatal rat [...] Read more.
Cerebral edema, primarily caused by disruption of the blood-brain barrier (BBB), is one of the serious complications associated with brain injury in neonatal hypoxic-ischemic encephalopathy (HIE). Our recent study demonstrated that the hypoxic-ischemic (HI) treatment significantly increased microRNA-210 (miR-210) in the neonatal rat brain and inhibition of miR-210 provided neuroprotection in neonatal HI brain injury. The present study aims to determine the role of miR-210 in the regulation of BBB integrity in the developing brain. miR-210 mimic was administered via intracerebroventricular injection (i.c.v.) into the brain of rat pups. Forty-eight hours after the injection, a modified Rice-Vannucci model was conducted to produce HI brain injury. Post-assays included cerebral edema analysis, western blotting, and immunofluorescence staining for serum immunoglobulin G (IgG) leakage. The results showed that miR-210 mimic exacerbated cerebral edema and IgG leakage into the brain parenchyma. In contrast, inhibition of miR-210 with its complementary locked nucleic acid oligonucleotides (miR-210-LNA) significantly reduced cerebral edema and IgG leakage. These findings suggest that miR-210 negatively regulates BBB integrity i n the neonatal brain. Mechanistically, the seed sequences of miR-210 were identified complementary to the 3′ untranslated region (3′ UTR) of the mRNA transcripts of tight junction protein occludin and adherens junction protein β-catenin, indicating downstream targets of miR-210. This was further validated by in vivo data showing that miR-210 mimic significantly reduced the expression of these junction proteins in rat pup brains. Of importance, miR-210-LNA preserved the expression of junction proteins occludin and β-catenin from neonatal HI insult. Altogether, the present study reveals a novel mechanism of miR-210 in impairing BBB integrity that contributes to cerebral edema formation after neonatal HI insult, and provides new insights in miR-210-LNA mediated neuroprotection in neonatal HI brain injury. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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Review

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Open AccessReview
The Type 3 Deiodinase: Epigenetic Control of Brain Thyroid Hormone Action and Neurological Function
Int. J. Mol. Sci. 2018, 19(6), 1804; https://doi.org/10.3390/ijms19061804 - 19 Jun 2018
Cited by 12
Abstract
Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and [...] Read more.
Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and receptors is critical to ensure specific levels of TH action in neural cells. The type 3 iodothyronine deiodinase (DIO3) inactivates THs and is highly present in the developing and adult brain, where it limits their availability and action. DIO3 deficiency in mice results in a host of neurodevelopmental and behavioral abnormalities, demonstrating the deleterious effects of TH excess, and revealing the critical role of DIO3 in the regulation of TH action in the brain. The fact the Dio3 is an imprinted gene and that its allelic expression pattern varies across brain regions and during development introduces an additional level of control to deliver specific levels of hormone action in the central nervous system (CNS). The sensitive epigenetic nature of the mechanisms controlling the genomic imprinting of Dio3 renders brain TH action particularly susceptible to disruption due to exogenous treatments and environmental exposures, with potential implications for the etiology of human neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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Open AccessReview
Epigenetics of Subcellular Structure Functioning in the Origin of Risk or Resilience to Comorbidity of Neuropsychiatric and Cardiometabolic Disorders
Int. J. Mol. Sci. 2018, 19(5), 1456; https://doi.org/10.3390/ijms19051456 - 14 May 2018
Cited by 7
Abstract
Mechanisms controlling mitochondrial function, protein folding in the endoplasmic reticulum (ER) and nuclear processes such as telomere length and DNA repair may be subject to epigenetic cues that relate the genomic expression and environmental exposures in early stages of life. They may also [...] Read more.
Mechanisms controlling mitochondrial function, protein folding in the endoplasmic reticulum (ER) and nuclear processes such as telomere length and DNA repair may be subject to epigenetic cues that relate the genomic expression and environmental exposures in early stages of life. They may also be involved in the comorbid appearance of cardiometabolic (CMD) and neuropsychiatric disorders (NPD) during adulthood. Mitochondrial function and protein folding in the endoplasmic reticulum are associated with oxidative stress and elevated intracellular calcium levels and may also underlie the vulnerability for comorbid CMD and NPD. Mitochondria provide key metabolites such as nicotinamide adenine dinucleotide (NAD+), ATP, α-ketoglutarate and acetyl coenzyme A that are required for many transcriptional and epigenetic processes. They are also a source of free radicals. On the other hand, epigenetic markers in nuclear DNA determine mitochondrial biogenesis. The ER is the subcellular organelle in which secretory proteins are folded. Many environmental factors stop the ability of cells to properly fold proteins and modify post-translationally secretory and transmembrane proteins leading to endoplasmic reticulum stress and oxidative stress. ER functioning may be epigenetically determined. Chronic ER stress is emerging as a key contributor to a growing list of human diseases, including CMD and NPD. Telomere loss causes chromosomal fusion, activation of the control of DNA damage-responses, unstable genome and altered stem cell function, which may underlie the comorbidity of CMD and NPD. The length of telomeres is related to oxidative stress and may be epigenetically programmed. Pathways involved in DNA repair may be epigenetically programmed and may contribute to diseases. In this paper, we describe subcellular mechanisms that are determined by epigenetic markers and their possible relation to the development of increased susceptibility to develop CMD and NPD. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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Open AccessReview
The Vast Complexity of the Epigenetic Landscape during Neurodevelopment: An Open Frame to Understanding Brain Function
Int. J. Mol. Sci. 2018, 19(5), 1333; https://doi.org/10.3390/ijms19051333 - 01 May 2018
Cited by 4
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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Open AccessReview
Epigenetic Programming of Synthesis, Release, and/or Receptor Expression of Common Mediators Participating in the Risk/Resilience for Comorbid Stress-Related Disorders and Coronary Artery Disease
Int. J. Mol. Sci. 2018, 19(4), 1224; https://doi.org/10.3390/ijms19041224 - 18 Apr 2018
Cited by 9
Abstract
Corticotrophin releasing factor, vasopressin, oxytocin, natriuretic hormones, angiotensin, neuregulins, some purinergic substances, and some cytokines contribute to the long-term modulation and restructuring of cardiovascular regulation networks and, at the same time, have relevance in situations of comorbid abnormal stress responses. The synthesis, release, [...] Read more.
Corticotrophin releasing factor, vasopressin, oxytocin, natriuretic hormones, angiotensin, neuregulins, some purinergic substances, and some cytokines contribute to the long-term modulation and restructuring of cardiovascular regulation networks and, at the same time, have relevance in situations of comorbid abnormal stress responses. The synthesis, release, and receptor expression of these mediators seem to be under epigenetic control since early stages of life, possibly underlying the comorbidity to coronary artery disease (CAD) and stress-related disorders (SRD). The exposure to environmental conditions, such as stress, during critical periods in early life may cause epigenetic programming modifying the development of pathways that lead to stable and long-lasting alterations in the functioning of these mediators during adulthood, determining the risk of or resilience to CAD and SRD. However, in contrast to genetic information, epigenetic marks may be dynamically altered throughout the lifespan. Therefore, epigenetics may be reprogrammed if the individual accepts the challenge to undertake changes in their lifestyle. Alternatively, epigenetics may remain fixed and/or even be inherited in the next generation. In this paper, we analyze some of the common neuroendocrine functions of these mediators in CAD and SRD and summarize the evidence indicating that they are under early programming to put forward the theoretical hypothesis that the comorbidity of these diseases might be epigenetically programmed and modified over the lifespan of the individual. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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Open AccessReview
Epigenomics of Major Depressive Disorders and Schizophrenia: Early Life Decides
Int. J. Mol. Sci. 2017, 18(8), 1711; https://doi.org/10.3390/ijms18081711 - 04 Aug 2017
Cited by 24
Abstract
Brain development is guided by the interactions between the genetic blueprint and the environment. Epigenetic mechanisms, especially DNA methylation, can mediate these interactions and may also trigger long-lasting adaptations in developmental programs that increase the risk of major depressive disorders (MDD) and schizophrenia [...] Read more.
Brain development is guided by the interactions between the genetic blueprint and the environment. Epigenetic mechanisms, especially DNA methylation, can mediate these interactions and may also trigger long-lasting adaptations in developmental programs that increase the risk of major depressive disorders (MDD) and schizophrenia (SCZ). Early life adversity is a major risk factor for MDD/SCZ and can trigger persistent genome-wide changes in DNA methylation at genes important to early, but also to mature, brain function, including neural proliferation, differentiation, and synaptic plasticity, among others. Moreover, genetic variations controlling dynamic DNA methylation in early life are thought to influence later epigenomic changes in SCZ. This finding corroborates the high genetic load and a neurodevelopmental origin of SCZ and shows that epigenetic responses to the environment are, at least in part, genetically controlled. Interestingly, genetic variants influencing DNA methylation are also enriched in risk variants from genome-wide association studies (GWAS) on SCZ supporting a role in neurodevelopment. Overall, epigenomic responses to early life adversity appear to be controlled to different degrees by genetics in MDD/SCZ, even though the potential reversibility of epigenomic processes may offer new hope for timely therapeutic interventions in MDD/SCZ. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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Open AccessReview
Histone Lysine Methylation and Neurodevelopmental Disorders
Int. J. Mol. Sci. 2017, 18(7), 1404; https://doi.org/10.3390/ijms18071404 - 30 Jun 2017
Cited by 21
Abstract
Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available [...] Read more.
Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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Other

Open AccessCase Report
Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature
Int. J. Mol. Sci. 2018, 19(1), 82; https://doi.org/10.3390/ijms19010082 - 28 Dec 2017
Cited by 6
Abstract
Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56–75% and 5–8% of the cases. To date, three KS patients with [...] Read more.
Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56–75% and 5–8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic KMT2D mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS-like traits. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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