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Epigenetic Regulation in Human Brain

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 21440

Special Issue Editor

The Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Interests: neurobiology; epigenetics; molecular biology; DNA methylation; DNA hydroxymethylaion; neuropsychiatric disorders; flow cytometry; high-throughput sequencing
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Special Issue Information

Dear Colleagues, 

The human brain is an organ of enormous complexity, composed of a multitude of cell types, including various populations of neuronal and glial cells. Epigenetics has been recognized for a long time as a group of molecular mechanisms that are essential in establishing and maintaining this complexity. Understanding the epigenetics of brain cell types is also necessary to uncover the mechanisms underlying nervous system disorders, which often display cell type-specific aetiology. However, in recent years, a number of methodological advances have allowed us to study brain epigenetics at cell-type resolution for the first time and brought the recognition of often vast and unexpected differences between the epigenomic profiles of brain cell populations. Despite this fast and promising progress, the field is currently wide open for new insights and discoveries, especially in the studies of brain development, disease, and ageing. A significantly more thorough understanding of neuroepigenetic mechanisms is also needed before we can efficiently transfer this line of research to the stage of therapeutic opportunities. In this Special Issue, we will highlight modern developments in the field of neuroepigenetics of human brain cell populations, in its relationship to brain development, health, and disease.

Dr. Alexey Kozlenkov
Guest Editor

Manuscript Submission Information

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Keywords

  • epigenetics
  • DNA methylation
  • histone modifications
  • human brain
  • neurons
  • glutamatergic neurons
  • glia

Related Special Issue

Published Papers (7 papers)

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Research

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18 pages, 2136 KiB  
Article
CRISPR/Cas9-Based Mutagenesis of Histone H3.1 in Spinal Dynorphinergic Neurons Attenuates Thermal Sensitivity in Mice
by Zoltán Mészár, Éva Kókai, Rita Varga, László Ducza, Tamás Papp, Monika Béresová, Marianna Nagy, Péter Szücs and Angelika Varga
Int. J. Mol. Sci. 2022, 23(6), 3178; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063178 - 15 Mar 2022
Cited by 2 | Viewed by 2130
Abstract
Burn injury is a trauma resulting in tissue degradation and severe pain, which is processed first by neuronal circuits in the spinal dorsal horn. We have recently shown that in mice, excitatory dynorphinergic (Pdyn) neurons play a pivotal role in the response to [...] Read more.
Burn injury is a trauma resulting in tissue degradation and severe pain, which is processed first by neuronal circuits in the spinal dorsal horn. We have recently shown that in mice, excitatory dynorphinergic (Pdyn) neurons play a pivotal role in the response to burn-injury-associated tissue damage via histone H3.1 phosphorylation-dependent signaling. As Pdyn neurons were mostly associated with mechanical allodynia, their involvement in thermonociception had to be further elucidated. Using a custom-made AAV9_mutH3.1 virus combined with the CRISPR/cas9 system, here we provide evidence that blocking histone H3.1 phosphorylation at position serine 10 (S10) in spinal Pdyn neurons significantly increases the thermal nociceptive threshold in mice. In contrast, neither mechanosensation nor acute chemonociception was affected by the transgenic manipulation of histone H3.1. These results suggest that blocking rapid epigenetic tagging of S10H3 in spinal Pdyn neurons alters acute thermosensation and thus explains the involvement of Pdyn cells in the immediate response to burn-injury-associated tissue damage. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Brain)
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11 pages, 2271 KiB  
Article
Prenatal Trimethyltin Exposure Induces Long-Term DNA Methylation Changes in the Male Mouse Hippocampus
by Soon-Ae Kim, Jung-Hoon Chai and Eun-Hye Jang
Int. J. Mol. Sci. 2021, 22(15), 8009; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158009 - 27 Jul 2021
Cited by 3 | Viewed by 1498
Abstract
Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the [...] Read more.
Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the total times spent in the center, corner, or border zones in the male prenatal TMT-exposed mice were less than those of control unexposed mice in the open-field test. Female TMT-exposed mice scored lower on total numbers of arm entries and percentages of alternations than controls in the Y-maze test with lower body weight. We found that only TMT-exposed males had fewer copies of mtDNA in the hippocampus and prefrontal cortex region than controls. Additional epigenetic changes, including increased 5-methyl cytosine/5-hydroxymethyl cytosine levels in the male TMT hippocampus, were observed. After methylation binding domain (MBD) sequencing, multiple signaling pathways related to metabolism and neurodevelopment, including FoxO signaling, were identified by pathway analysis for differentially methylated regions (DMRs). Increased FOXO3 and decreased ASCL1 expression were also observed in male TMT hippocampi. This study suggests that sex differences and epigenetics should be more carefully considered in prenatal toxicology studies. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Brain)
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17 pages, 10414 KiB  
Article
Epigenetic Consequences of in Utero Exposure to Rosuvastatin: Alteration of Histone Methylation Patterns in Newborn Rat Brains
by Karolina Dulka, Melinda Szabo, Noémi Lajkó, István Belecz, Zsófia Hoyk and Karoly Gulya
Int. J. Mol. Sci. 2021, 22(7), 3412; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073412 - 26 Mar 2021
Cited by 3 | Viewed by 2229
Abstract
Rosuvastatin (RST) is primarily used to treat high cholesterol levels. As it has potentially harmful but not well-documented effects on embryos, RST is contraindicated during pregnancy. To demonstrate whether RST could induce molecular epigenetic events in the brains of newborn rats, pregnant mothers [...] Read more.
Rosuvastatin (RST) is primarily used to treat high cholesterol levels. As it has potentially harmful but not well-documented effects on embryos, RST is contraindicated during pregnancy. To demonstrate whether RST could induce molecular epigenetic events in the brains of newborn rats, pregnant mothers were treated daily with oral RST from the 11th day of pregnancy for 10 days (or until delivery). On postnatal day 1, the brains of the control and RST-treated rats were removed for Western blot or immunohistochemical analyses. Several antibodies that recognize different methylation sites for H2A, H2B, H3, and H4 histones were quantified. Analyses of cell-type-specific markers in the newborn brains demonstrated that prenatal RST administration did not affect the composition and cell type ratios as compared to the controls. Prenatal RST administration did, however, induce a general, nonsignificant increase in H2AK118me1, H2BK5me1, H3, H3K9me3, H3K27me3, H3K36me2, H4, H4K20me2, and H4K20me3 levels, compared to the controls. Moreover, significant changes were detected in the number of H3K4me1 and H3K4me3 sites (134.3% ± 19.2% and 127.8% ± 8.5% of the controls, respectively), which are generally recognized as transcriptional activators. Fluorescent/confocal immunohistochemistry for cell-type-specific markers and histone methylation marks on tissue sections indicated that most of the increase at these sites belonged to neuronal cell nuclei. Thus, prenatal RST treatment induces epigenetic changes that could affect neuronal differentiation and development. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Brain)
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16 pages, 1868 KiB  
Article
Downregulation of the Polycomb-Associated Methyltransferase Ezh2 during Maturation of Hippocampal Neurons Is Mediated by MicroRNAs Let-7 and miR-124
by Laura Guajardo, Rodrigo Aguilar, Fernando J. Bustos, Gino Nardocci, Rodrigo A. Gutiérrez, Brigitte van Zundert and Martin Montecino
Int. J. Mol. Sci. 2020, 21(22), 8472; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228472 - 11 Nov 2020
Cited by 6 | Viewed by 2050
Abstract
Ezh2 is a catalytic subunit of the polycomb repressive complex 2 (PRC2) which mediates epigenetic gene silencing through depositing the mark histone H3 lysine 27 trimethylation (H3K27me3) at target genomic sequences. Previous studies have demonstrated that Enhancer of Zeste Homolog 2 (Ezh2) was [...] Read more.
Ezh2 is a catalytic subunit of the polycomb repressive complex 2 (PRC2) which mediates epigenetic gene silencing through depositing the mark histone H3 lysine 27 trimethylation (H3K27me3) at target genomic sequences. Previous studies have demonstrated that Enhancer of Zeste Homolog 2 (Ezh2) was differentially expressed during maturation of hippocampal neurons; in immature neurons, Ezh2 was abundantly expressed, whereas in mature neurons the expression Ezh2 was significantly reduced. Here, we report that Ezh2 is downregulated by microRNAs (miRs) that are expressed during the hippocampal maturation process. We show that, in mature hippocampal neurons, lethal-7 (let-7) and microRNA-124 (miR-124) are robustly expressed and can target cognate motifs at the 3′-UTR of the Ezh2 gene sequence to downregulate Ezh2 expression. Together, these data demonstrate that the PRC2 repressive activity during hippocampal maturation is controlled through a post-transcriptional mechanism that mediates Ezh2 downregulation in mature neurons. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Brain)
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Review

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19 pages, 4754 KiB  
Review
A Systematic Review of Circulatory microRNAs in Major Depressive Disorder: Potential Biomarkers for Disease Prognosis
by Madiha Rasheed, Rabia Asghar, Sundas Firdoos, Nadeem Ahmad, Amina Nazir, Kakar Mohib Ullah, Noumin Li, Fengyuan Zhuang, Zixuan Chen and Yulin Deng
Int. J. Mol. Sci. 2022, 23(3), 1294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031294 - 24 Jan 2022
Cited by 12 | Viewed by 3551
Abstract
Major depressive disorder (MDD) is a neuropsychiatric disorder, which remains challenging to diagnose and manage due to its complex endophenotype. In this aspect, circulatory microRNAs (cimiRNAs) offer great potential as biomarkers and may provide new insights for MDD diagnosis. Therefore, we systemically reviewed [...] Read more.
Major depressive disorder (MDD) is a neuropsychiatric disorder, which remains challenging to diagnose and manage due to its complex endophenotype. In this aspect, circulatory microRNAs (cimiRNAs) offer great potential as biomarkers and may provide new insights for MDD diagnosis. Therefore, we systemically reviewed the literature to explore various cimiRNAs contributing to MDD diagnosis and underlying molecular pathways. A comprehensive literature survey was conducted, employing four databases from 2012 to January 2021. Out of 1004 records, 157 reports were accessed for eligibility criteria, and 32 reports meeting our inclusion criteria were considered for in-silico analysis. This study identified 99 dysregulated cimiRNAs in MDD patients, out of which 20 cimiRNAs found in multiple reports were selected for in-silico analysis. KEGG pathway analysis indicated activation of ALS, MAPK, p53, and P13K-Akt signaling pathways, while gene ontology analysis demonstrated that most protein targets were associated with transcription. In addition, chromosomal location analysis showed clustering of dysregulated cimiRNAs at proximity 3p22-p21, 9q22.32, and 17q11.2, proposing their coregulation with specific transcription factors primarily involved in MDD physiology. Further analysis of transcription factor sites revealed the existence of HIF-1, REST, and TAL1 in most cimiRNAs. These transcription factors are proposed to target genes linked with MDD, hypothesizing that first-wave cimiRNA dysregulation may trigger the second wave of transcription-wide changes, altering the protein expressions of MDD-affected cells. Overall, this systematic review presented a list of dysregulated cimiRNAs in MDD, notably miR-24-3p, let 7a-5p, miR-26a-5p, miR135a, miR-425-3p, miR-132, miR-124 and miR-16-5p as the most prominent cimiRNAs. However, various constraints did not permit us to make firm conclusions on the clinical significance of these cimiRNAs, suggesting the need for more research on single blood compartment to identify the biomarker potential of consistently dysregulated cimiRNAs in MDD, as well as the therapeutic implications of these in-silico insights. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Brain)
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28 pages, 1058 KiB  
Review
The miRNome of Depression
by Dariusz Żurawek and Gustavo Turecki
Int. J. Mol. Sci. 2021, 22(21), 11312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111312 - 20 Oct 2021
Cited by 22 | Viewed by 4155
Abstract
Depression is an effect of complex interactions between genetic, epigenetic and environmental factors. It is well established that stress responses are associated with multiple modest and often dynamic molecular changes in the homeostatic balance, rather than with a single genetic factor that has [...] Read more.
Depression is an effect of complex interactions between genetic, epigenetic and environmental factors. It is well established that stress responses are associated with multiple modest and often dynamic molecular changes in the homeostatic balance, rather than with a single genetic factor that has a strong phenotypic penetration. As depression is a multifaceted phenotype, it is important to study biochemical pathways that can regulate the overall allostasis of the brain. One such biological system that has the potential to fine-tune a multitude of diverse molecular processes is RNA interference (RNAi). RNAi is an epigenetic process showing a very low level of evolutionary diversity, and relies on the posttranscriptional regulation of gene expression using, in the case of mammals, primarily short (17–23 nucleotides) noncoding RNA transcripts called microRNAs (miRNA). In this review, our objective was to examine, summarize and discuss recent advances in the field of biomedical and clinical research on the role of miRNA-mediated regulation of gene expression in the development of depression. We focused on studies investigating post-mortem brain tissue of individuals with depression, as well as research aiming to elucidate the biomarker potential of miRNAs in depression and antidepressant response. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Brain)
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27 pages, 924 KiB  
Review
Chromatin Profiling Techniques: Exploring the Chromatin Environment and Its Contributions to Complex Traits
by Anjali Chawla, Corina Nagy and Gustavo Turecki
Int. J. Mol. Sci. 2021, 22(14), 7612; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147612 - 16 Jul 2021
Cited by 5 | Viewed by 4657
Abstract
The genetic architecture of complex traits is multifactorial. Genome-wide association studies (GWASs) have identified risk loci for complex traits and diseases that are disproportionately located at the non-coding regions of the genome. On the other hand, we have just begun to understand the [...] Read more.
The genetic architecture of complex traits is multifactorial. Genome-wide association studies (GWASs) have identified risk loci for complex traits and diseases that are disproportionately located at the non-coding regions of the genome. On the other hand, we have just begun to understand the regulatory roles of the non-coding genome, making it challenging to precisely interpret the functions of non-coding variants associated with complex diseases. Additionally, the epigenome plays an active role in mediating cellular responses to fluctuations of sensory or environmental stimuli. However, it remains unclear how exactly non-coding elements associate with epigenetic modifications to regulate gene expression changes and mediate phenotypic outcomes. Therefore, finer interrogations of the human epigenomic landscape in associating with non-coding variants are warranted. Recently, chromatin-profiling techniques have vastly improved our understanding of the numerous functions mediated by the epigenome and DNA structure. Here, we review various chromatin-profiling techniques, such as assays of chromatin accessibility, nucleosome distribution, histone modifications, and chromatin topology, and discuss their applications in unraveling the brain epigenome and etiology of complex traits at tissue homogenate and single-cell resolution. These techniques have elucidated compositional and structural organizing principles of the chromatin environment. Taken together, we believe that high-resolution epigenomic and DNA structure profiling will be one of the best ways to elucidate how non-coding genetic variations impact complex diseases, ultimately allowing us to pinpoint cell-type targets with therapeutic potential. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Human Brain)
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