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Biology
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How Epigenetics Shapes the Nervous System
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How Epigenetics Shapes the Nervous System

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Neuroscience".

Deadline for manuscript submissions: closed (31 March 2026) | Viewed by 12516

Special Issue Editor

Dr. Andrea Stoccoro

E-Mail Website
Guest Editor
Medical Genetics Laboratories, Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
Interests: neurobiology; neurodegeneration; epigenetic biomarkers; environmental factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, regulate gene expression, influencing neural differentiation, synaptic remodeling, and cognitive processes. These mechanisms play a crucial role in the development, function, and plasticity of the nervous system. Emerging evidence also links altered epigenetic regulation to neurological disorders, neurodegenerative diseases, and psychiatric conditions, offering novel insights into disease pathogenesis and potential therapeutic strategies. Notably, neurodevelopmental disorders caused by germline mutations in genes encoding epigenetic regulators, known as chromatinopathies, underscore the profound impact of epigenetic mechanisms on central nervous system function.

This Special Issue aims to bring together cutting-edge research and reviews exploring the diverse roles of epigenetic modifications in neural development, function, and disease. We welcome contributions exploring the fundamental mechanisms of neuro-epigenetics and translational research investigating altered epigenetic mechanisms underlying neurological disorders, as well as studies exploring the therapeutic potential of targeting the epigenome. Additionally, we encourage contributions examining the impact of environmental and early-life factors on epigenetic modifications in the nervous system, along with updated reviews and systematic reviews on specific aspects of neuro-epigenetics. By assembling a comprehensive collection of studies, we seek to advance our understanding of how epigenetics shapes nervous system biology and contributes to neuropathology, paving the way for novel diagnostic and therapeutic strategies.

We look forward to receiving your contributions.

Dr. Andrea Stoccoro
Guest Editor

Manuscript Submission Information

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Keywords

  • nervous system
  • epigenetics
  • DNA methylation
  • histone tail modifications
  • non-coding RNAs
  • neurological disorders
  • neurodegenerative diseases
  • biomarkers
  • environmental epigenetics

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Published Papers (4 papers)

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Research

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22 pages, 1654 KB  
Article
Transgenerational Epigenetic Inheritance of Early-Life Stress from Grand-Dams Through Paternal Gametes: Impaired Social Cognition and Reduced Reactivity to Aversive Predictors in DAT-HET Rats
by Eleonora D’Antonio, Gioia Zanfino, Concetto Puzzo, Micaela Capobianco, Francesco Mannella, Vincenzo De Laurenzi, Giuseppe Curcio and Walter Adriani
Biology 2025, 14(9), 1229; https://doi.org/10.3390/biology14091229 - 9 Sep 2025
Viewed by 3446
Abstract
Transgenerational epigenetic inheritance has emerged as a compelling mechanism by which early-life stress can shape behavior in descendants with no direct exposure to trauma. However, whether such heritable modifications affect subtle behavioral phenotypes, like processing of social and emotional stimuli, remains poorly understood. [...] Read more.
Transgenerational epigenetic inheritance has emerged as a compelling mechanism by which early-life stress can shape behavior in descendants with no direct exposure to trauma. However, whether such heritable modifications affect subtle behavioral phenotypes, like processing of social and emotional stimuli, remains poorly understood. In this study, we investigated the behavioral profile of fourth-generation heterozygous dopamine-transporter (DAT-HET) rats. Compared to control (SX) rats, our experimental group (labelled SIKK) consisted of animals (at G4, F3) born from MIK sires (at G3, F2), who descended from grand-dams (at G2, F1) who were in turn exposed to early-life maltreatment by their own DAT-KO mothers (the great-grand-dams, at G1, F0). To probe inhibitory control and social cognition, we employed the signaled licking / avoidance of punishment (SLAP) task, the elicited preference test (EPT), and the social recognition test (SRT). In the SLAP task, SIKK rats exhibited slower acquisition of passive avoidance, suggesting dampened sensitivity to predictive aversive cues. In the EPT, wild-type focal rats displayed a clear preference for SX over SIKK conspecifics, indicating reduced social appeal of epigenetically altered animals. In the SRT, SX rats successfully discriminated between a novel and a familiar DAT-KO conspecific, while SIKK rats failed to do so, revealing impaired social cognition. Together, these findings indicate that, despite the absence of direct trauma in their infancy, SIKK rats exhibit a distinct behavioral phenotype characterized by increased reactivity to threat and deficits in social preferences and cognition. These alterations reflect inherited dysfunctions in limbic dopaminergic circuits, particularly within PFC. Our study highlights how an ancestor’s adversity can shape adaptive behavior in future generations, providing a powerful model for understanding the biological basis of vulnerability to psychiatric disorders. Full article
(This article belongs to the Special Issue How Epigenetics Shapes the Nervous System)
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Review

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18 pages, 780 KB  
Review
The Convergence of Early-Life Stress and Autism Spectrum Disorder on the Epigenetics of Genes Key to the HPA Axis
by Edric Han, Katherine A. Canada, Meghan H. Puglia, Kevin A. Pelphrey and Tanya M. Evans
Biology 2026, 15(1), 66; https://doi.org/10.3390/biology15010066 - 30 Dec 2025
Cited by 1 | Viewed by 3912
Abstract
Autism spectrum disorder (ASD) arises from complex genetic and environmental influences. Despite its prevalence and being the focus of study for several decades, its causes and their underlying mechanisms are still not fully understood. However, one consistent causal mechanism of interest is epigenetic [...] Read more.
Autism spectrum disorder (ASD) arises from complex genetic and environmental influences. Despite its prevalence and being the focus of study for several decades, its causes and their underlying mechanisms are still not fully understood. However, one consistent causal mechanism of interest is epigenetic modification. While some risk factors, such as maternal stress, nutrition, and environmental toxins, have a more established epigenetic connection, early-life stress (ELS) in the postnatal years is less studied but may be just as impactful in terms of phenotypic outcomes. A major intermediary between ELS and ASD is likely the hypothalamic–pituitary–adrenal axis (HPA axis), which has been shown to be epigenetically modified by ELS and whose genes and dysfunction overlap with ASD genes and symptoms. In this narrative review, we synthesize human and animal evidence to examine the relationships between ELS and ASD through epigenetic regulation of a non-exhaustive list of autism candidate genes involved in the HPA axis, including NR3C1, FKBP5, MECP2, GAD1, RELN, SHANK3, OXTR, and BDNF. We discuss how ELS-induced epigenetics may modulate HPA axis negative feedback, and how epigenetic alterations in this pathway and associated genes could affect ASD phenotypes. Full article
(This article belongs to the Special Issue How Epigenetics Shapes the Nervous System)
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34 pages, 1750 KB  
Review
Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective
by Arefa Yeasmin and Mariana P. Torrente
Biology 2025, 14(11), 1556; https://doi.org/10.3390/biology14111556 - 6 Nov 2025
Viewed by 2023
Abstract
DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are [...] Read more.
DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson’s Disease, Alzheimer’s Diseases, Multiple Sclerosis, and Huntington’s Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival. Full article
(This article belongs to the Special Issue How Epigenetics Shapes the Nervous System)
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22 pages, 1538 KB  
Review
Multi-Faceted Role of Histone Methyltransferase Enhancer of Zeste 2 (EZH2) in Neuroinflammation and Emerging Targeting Options
by Sotirios Moraitis and Christina Piperi
Biology 2025, 14(7), 749; https://doi.org/10.3390/biology14070749 - 23 Jun 2025
Cited by 2 | Viewed by 2592
Abstract
Neuroinflammation, a complex nervous system response to brain injury and other pathological stimuli, exhibits a common denominator role in the pathogenesis of neurological disorders and their progression. Among several regulators of neuroinflammation, epigenetic mechanisms with particular emphasis on histone methylation have a prominent [...] Read more.
Neuroinflammation, a complex nervous system response to brain injury and other pathological stimuli, exhibits a common denominator role in the pathogenesis of neurological disorders and their progression. Among several regulators of neuroinflammation, epigenetic mechanisms with particular emphasis on histone methylation have a prominent role by altering the expression of specific genes involved in the onset and progression of neuroinflammation. The Enhancer of Zeste 2 (EZH2) histone lysine methyltransferase is a multi-faceted and context-dependent regulator of immune response and neural cell function, significantly involved in the underlying mechanisms of neuroinflammation, such as inflammatory gene expression, astrocyte function, microglial activation, BBB integrity, and interactions with non-coding RNAs. Herein, we explore the intricate implication of EZH2 activity in the onset of neuroinflammation and associated pathological conditions, and discuss its potential as a therapeutic target. Currently available EZH2 inhibitors with neuroprotective effects are also addressed in an effort to reveal novel strategies for managing neuroinflammatory conditions, and potentially improving neurological health. Full article
(This article belongs to the Special Issue How Epigenetics Shapes the Nervous System)
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