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Biomolecules
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Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways
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Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 5639

Special Issue Editors

Dr. Maria Giuseppina Miano

E-Mail Website
Guest Editor
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council, 80131 Naples, Italy
Interests: intellectual disability and developmental epileptic encephalopathies; ARX-KDM5C; disease models; convergent transcriptional pathways
Special Issues, Collections and Topics in MDPI journals
Dr. Floriana Della Ragione

E-Mail Website
Guest Editor
Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR Via P. Castellino 111, 80131 Naples, Italy
Interests: human genetics; Rett syndrome; chromatin diseases; epigenetics; epigenomics; MeCP2-mediated molecular mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodevelopmental disorders (NDDs) are a group of genetically heterogeneous diseases in which the development of the central nervous system is disturbed. Identification and functional studies of a large number of NDD genes have been performed over the years, and specific interconnected disease pathways have been discovered. In addition, several NDDs are caused by dysfunctions of epigenetic factors, which often result in large-scale molecular alterations. It is conceivable that targeting a common node in such a disease network could consent to interfering with multiple related NDDs at once.

This Special Issue will focus on distinct and complementary aspects of NDD research: analysis of the molecular mechanisms underlying the intersection of multiple NDD genes involved in specialized brain functions (e.g., chromatin remodeling, neurogenesis, synaptic pruning, neurotransmission, energy metabolism); identification of biomarkers helpful to follow disease onset and age-dependent evolution; and discovery of drugs capable of modulating specific disease networks with encouraging outcomes in cellular and animal models.

Original manuscripts and reviews dealing with any genetic and epigenetic aspect of NDDs and innovative strategies for prevention, diagnosis, and therapeutical intervention are welcome.

Dr. Maria Giuseppina Miano
Dr. Floriana Della Ragione
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • genetics and epigenetics
  • convergent disease pathways
  • biomarkers
  • molecular therapies

Published Papers (3 papers)

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Research

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18 pages, 2636 KiB  
Article
ICF1-Syndrome-Associated DNMT3B Mutations Prevent De Novo Methylation at a Subset of Imprinted Loci during iPSC Reprogramming
by Ankit Verma, Varsha Poondi Krishnan, Francesco Cecere, Emilia D’Angelo, Vincenzo Lullo, Maria Strazzullo, Sara Selig, Claudia Angelini, Maria R. Matarazzo and Andrea Riccio
Biomolecules 2023, 13(12), 1717; https://doi.org/10.3390/biom13121717 - 28 Nov 2023
Viewed by 931
Abstract
Parent-of-origin-dependent gene expression of a few hundred human genes is achieved by differential DNA methylation of both parental alleles. This imprinting is required for normal development, and defects in this process lead to human disease. Induced pluripotent stem cells (iPSCs) serve as a [...] Read more.
Parent-of-origin-dependent gene expression of a few hundred human genes is achieved by differential DNA methylation of both parental alleles. This imprinting is required for normal development, and defects in this process lead to human disease. Induced pluripotent stem cells (iPSCs) serve as a valuable tool for in vitro disease modeling. However, a wave of de novo DNA methylation during reprogramming of iPSCs affects DNA methylation, thus limiting their use. The DNA methyltransferase 3B (DNMT3B) gene is highly expressed in human iPSCs; however, whether the hypermethylation of imprinted loci depends on DNMT3B activity has been poorly investigated. To explore the role of DNMT3B in mediating de novo DNA methylation at imprinted DMRs, we utilized iPSCs generated from patients with immunodeficiency, centromeric instability, facial anomalies type I (ICF1) syndrome that harbor biallelic hypomorphic DNMT3B mutations. Using a whole-genome array-based approach, we observed a gain of methylation at several imprinted loci in control iPSCs but not in ICF1 iPSCs compared to their parental fibroblasts. Moreover, in corrected ICF1 iPSCs, which restore DNMT3B enzymatic activity, imprinted DMRs did not acquire control DNA methylation levels, in contrast to the majority of the hypomethylated CpGs in the genome that were rescued in the corrected iPSC clones. Overall, our study indicates that DNMT3B is responsible for de novo methylation of a subset of imprinted DMRs during iPSC reprogramming and suggests that imprinting is unstable during a specific time window of this process, after which the epigenetic state at these regions becomes resistant to perturbation. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways)
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14 pages, 1901 KiB  
Article
Blood–Brain Barrier Integrity Is Perturbed in a Mecp2-Null Mouse Model of Rett Syndrome
by Giuseppe Pepe, Salvatore Fioriniello, Federico Marracino, Luca Capocci, Vittorio Maglione, Maurizio D’Esposito, Alba Di Pardo and Floriana Della Ragione
Biomolecules 2023, 13(4), 606; https://doi.org/10.3390/biom13040606 - 28 Mar 2023
Cited by 4 | Viewed by 2490
Abstract
Rett syndrome (RTT, online MIM 312750) is a devastating neurodevelopmental disorder characterized by motor and cognitive disabilities. It is mainly caused by pathogenetic variants in the X-linked MECP2 gene, encoding an epigenetic factor crucial for brain functioning. Despite intensive studies, the RTT pathogenetic [...] Read more.
Rett syndrome (RTT, online MIM 312750) is a devastating neurodevelopmental disorder characterized by motor and cognitive disabilities. It is mainly caused by pathogenetic variants in the X-linked MECP2 gene, encoding an epigenetic factor crucial for brain functioning. Despite intensive studies, the RTT pathogenetic mechanism remains to be fully elucidated. Impaired vascular function has been previously reported in RTT mouse models; however, whether an altered brain vascular homeostasis and the subsequent blood–brain barrier (BBB) breakdown occur in RTT and contribute to the disease-related cognitive impairment is still unknown. Interestingly, in symptomatic Mecp2-null (Mecp2-/y, Mecp2tm1.1Bird) mice, we found enhanced BBB permeability associated with an aberrant expression of the tight junction proteins Ocln and Cldn-5 in different brain areas, in terms of both transcript and protein levels. Additionally, Mecp2-null mice showed an altered expression of different genes encoding factors with a role in the BBB structure and function, such as Cldn3, Cldn12, Mpdz, Jam2, and Aqp4. With this study, we provide the first evidence of impaired BBB integrity in RTT and highlight a potential new molecular hallmark of the disease that might open new perspectives for the setting-up of novel therapeutic strategies. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways)
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Review

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17 pages, 2745 KiB  
Review
Suberoylanilide Hydroxamic Acid (SAHA) Is a Driver Molecule of Neuroplasticity: Implication for Neurological Diseases
by Lucia Verrillo, Rosita Di Palma, Alberto de Bellis, Denise Drongitis and Maria Giuseppina Miano
Biomolecules 2023, 13(9), 1301; https://doi.org/10.3390/biom13091301 - 24 Aug 2023
Viewed by 1256
Abstract
Neuroplasticity is a crucial property of the central nervous system to change its activity in response to intrinsic or extrinsic stimuli. This is mainly achieved through the promotion of changes in the epigenome. One of the epi-drivers priming this process is suberoylanilide hydroxamic [...] Read more.
Neuroplasticity is a crucial property of the central nervous system to change its activity in response to intrinsic or extrinsic stimuli. This is mainly achieved through the promotion of changes in the epigenome. One of the epi-drivers priming this process is suberoylanilide hydroxamic acid (SAHA or Vorinostat), a pan-histone deacetylase inhibitor that modulates and promotes neuroplasticity in healthy and disease conditions. Knowledge of the specific molecular changes induced by this epidrug is an important area of neuro-epigenetics for the identification of new compounds to treat cognition impairment and/or epilepsy. In this review, we summarize the findings obtained in cellular and animal models of various brain disorders, highlighting the multiple mechanisms activated by SAHA, such as improvement of memory, learning and behavior, and correction of faulty neuronal functioning. Supporting this evidence, in vitro and in vivo data underline how SAHA positively regulates the expression of neuronal genes and microtubule dynamics, induces neurite outgrowth and spine density, and enhances synaptic transmission and potentiation. In particular, we outline studies regarding neurodevelopmental disorders with pharmaco-resistant seizures and/or severe cognitive impairment that to date lack effective drug treatments in which SAHA could ameliorate defective neuroplasticity. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways)
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