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Epigenetics of Fragile X and Other Neurodevelopmental Disorders
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Epigenetics of Fragile X and Other Neurodevelopmental Disorders

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (10 July 2022) | Viewed by 15969

Special Issue Editors

Prof. Dr. Giovanni Neri

E-Mail Website
Guest Editor
Sezione di Medicina Genomica, Dipartimento Scienze della Vita e Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Interests: fragile X syndrome; X-linked intellectual disability; RASopathies; overgrowth syndromes
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Fiorella Gurrieri

E-Mail Website
Guest Editor
Unit of Medical Genetics, University Campus Bio-Medico of Rome, 00128 Rome, Italy
Interests: autism spectrum disorders; intellectual disabilities; epigenetics

Special Issue Information

Dear Colleagues,

We would like to invite you to participate in this Special Issue, "Epigenetics of Fragile X and Other Neurodevelopmental Disorders".

In recent years, the field of epigenetics has seen a tremendous expansion as testified by the number of published papers and even the creation of dedicated journals. Epigenetics is a set of regulatory mechanisms affecting gene activity and a signature thereof, acting primarily through DNA methylation and histone acetylation. Mutations impinging on these mechanisms can cause genetic diseases. At the same time, the reversibility of epigenetic marks opens the way to the possibility of treating these diseases through drugs that affect these marks.

More recently we have witnessed the extension of epigenetics to the RNA world. The activity of mRNAs can be affected by adenosine methylation, and transcriptome-wide methylation mapping is providing a methylation profile of cellular RNAs, known as the epitranscriptome.

The purpose of this Special Issue is to host research and review papers on current molecular understanding of the role epigenetic derangements in causing heritable neurodevelopmental disorders and its corollaries towards the establishment of “epigenetic therapies”.

Prof. Dr. Giovanni Neri
Prof. Dr. Fiorella Gurrieri
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 papers will be 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. Genes 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 2000 CHF (Swiss Francs), please note that for papers submitted after 31 December 2021, an APC of 2400 CHF applies. 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

  • neurodevelopmental disorders
  • epigenetics
  • DNA methylation
  • RNA methylation
  • histone acetylation
  • transcriptomics
  • epitranscriptomics
  • chromatinopaties
  • regulation of gene expression

Published Papers (7 papers)

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13 pages, 451 KiB  
Article
Maternal Epigenetic Dysregulation as a Possible Risk Factor for Neurodevelopmental Disorders
by Carla Lintas, Ilaria Cassano, Alessia Azzarà, Maria Grazia Stigliano, Chiara Gregorj, Roberto Sacco, Andrea Stoccoro, Fabio Coppedè and Fiorella Gurrieri
Genes 2023, 14(3), 585; https://doi.org/10.3390/genes14030585 - 25 Feb 2023
Cited by 2 | Viewed by 1447
Abstract
Neurodevelopmental Disorders (NDs) are a heterogeneous group of disorders and are considered multifactorial diseases with both genetic and environmental components. Epigenetic dysregulation driven by adverse environmental factors has recently been documented in neurodevelopmental disorders as the possible etiological agent for their onset. However, [...] Read more.
Neurodevelopmental Disorders (NDs) are a heterogeneous group of disorders and are considered multifactorial diseases with both genetic and environmental components. Epigenetic dysregulation driven by adverse environmental factors has recently been documented in neurodevelopmental disorders as the possible etiological agent for their onset. However, most studies have focused on the epigenomes of the probands rather than on a possible epigenetic dysregulation arising in their mothers and influencing neurodevelopment during pregnancy. The aim of this research was to analyze the methylation profile of four well-known genes involved in neurodevelopment (BDNF, RELN, MTHFR and HTR1A) in the mothers of forty-five age-matched AS (Asperger Syndrome), ADHD (Attention Deficit Hyperactivity Disorder) and typically developing children. We found a significant increase of methylation at the promoter of the RELN and HTR1A genes in AS mothers compared to ADHD and healthy control mothers. For the MTHFR gene, promoter methylation was significantly higher in AS mothers compared to healthy control mothers only. The observed dysregulation in AS mothers could potentially contribute to the affected condition in their children deserving further investigation. Full article
(This article belongs to the Special Issue Epigenetics of Fragile X and Other Neurodevelopmental Disorders)
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14 pages, 1307 KiB  
Article
Profiling Genome-Wide DNA Methylation in Children with Autism Spectrum Disorder and in Children with Fragile X Syndrome
by Mittal Jasoliya, Jianlei Gu, Reem R. AlOlaby, Blythe Durbin-Johnson, Frederic Chedin and Flora Tassone
Genes 2022, 13(10), 1795; https://doi.org/10.3390/genes13101795 - 04 Oct 2022
Cited by 5 | Viewed by 2373
Abstract
Autism spectrum disorder (ASD) is an early onset, developmental disorder whose genetic cause is heterogeneous and complex. In total, 70% of ASD cases are due to an unknown etiology. Among the monogenic causes of ASD, fragile X syndrome (FXS) accounts for 2–4% of [...] Read more.
Autism spectrum disorder (ASD) is an early onset, developmental disorder whose genetic cause is heterogeneous and complex. In total, 70% of ASD cases are due to an unknown etiology. Among the monogenic causes of ASD, fragile X syndrome (FXS) accounts for 2–4% of ASD cases, and 60% of individuals with FXS present with ASD. Epigenetic changes, specifically DNA methylation, which modulates gene expression levels, play a significant role in the pathogenesis of both disorders. Thus, in this study, using the Human Methylation EPIC Bead Chip, we examined the global DNA methylation profiles of biological samples derived from 57 age-matched male participants (2–6 years old), including 23 subjects with ASD, 23 subjects with FXS with ASD (FXSA) and 11 typical developing (TD) children. After controlling for technical variation and white blood cell composition, using the conservatory threshold of the false discovery rate (FDR ≤ 0.05), in the three comparison groups, TD vs. AD, TD vs. FXSA and ASD vs. FXSA, we identified 156, 79 and 3100 differentially methylated sites (DMS), and 14, 13 and 263 differential methylation regions (DMRs). Interestingly, several genes differentially methylated among the three groups were among those listed in the SFARI Gene database, including the PAK2, GTF2I and FOXP1 genes important for brain development. Further, enrichment analyses identified pathways involved in several functions, including synaptic plasticity. Our preliminary study identified a significant role of altered DNA methylation in the pathology of ASD and FXS, suggesting that the characterization of a DNA methylation signature may help to unravel the pathogenicity of FXS and ASD and may help the development of an improved diagnostic classification of children with ASD and FXSA. In addition, it may pave the way for developing therapeutic interventions that could reverse the altered methylome profile in children with neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Epigenetics of Fragile X and Other Neurodevelopmental Disorders)
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9 pages, 1079 KiB  
Article
The Impact of the COVID-19 Pandemic on School-Aged Children with Fragile X Syndrome
by Hailey Silver, Hilary Rosselot, Rebecca Shaffer and Reymundo Lozano
Genes 2022, 13(9), 1666; https://doi.org/10.3390/genes13091666 - 17 Sep 2022
Cited by 2 | Viewed by 1780
Abstract
The pandemic caused by the spread of the coronavirus disease (COVID-19), beginning in early 2020, had an impact beyond anything experienced in recent history. People with Fragile X Syndrome (FXS), the leading known heritable cause of ASD and intellectual disability, were uniquely vulnerable [...] Read more.
The pandemic caused by the spread of the coronavirus disease (COVID-19), beginning in early 2020, had an impact beyond anything experienced in recent history. People with Fragile X Syndrome (FXS), the leading known heritable cause of ASD and intellectual disability, were uniquely vulnerable to pandemic-related changes. This study surveyed parent perspectives of the impact on 33 school-aged children with FXS across daily living skills, education, therapies, behaviors, health visits, and mask wearing. Academic performance was perceived to have decreased in most of the children (58%). Students in online school had the most reports of decline and those in person had the most reported improvement. Parents were significantly more satisfied with services that remained in person compared to those delivered online or in hybrid settings. Additionally, depression (75%), sleep problems (80%), attention problems (73%), and social skills (61%) were reported to have worsened the most. Parents reported that in addition to continuing with a structured schedule, the most helpful strategies were increasing face-to-face social interactions and outdoor activities. Future research should explore strategies to help online interventions and education to be more successful with individuals with FXS, given this may become a resource for families not geographically able to access in-person resources. Full article
(This article belongs to the Special Issue Epigenetics of Fragile X and Other Neurodevelopmental Disorders)
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8 pages, 937 KiB  
Article
Parent and Caregiver Perspectives towards Cannabidiol as a Treatment for Fragile X Syndrome
by Madison Maertens, Hailey Silver, Jayne Dixon Weber, Hillary Rosselot and Reymundo Lozano
Genes 2022, 13(9), 1594; https://doi.org/10.3390/genes13091594 - 06 Sep 2022
Cited by 2 | Viewed by 1850
Abstract
Cannabidiol (CBD) is a non-intoxicating chemical in cannabis plants that is being investigated as a candidate for treatment in Fragile X Syndrome (FXS), a leading known cause of inherited intellectual developmental disability. Studies have shown that CBD can reduce symptoms such as anxiety, [...] Read more.
Cannabidiol (CBD) is a non-intoxicating chemical in cannabis plants that is being investigated as a candidate for treatment in Fragile X Syndrome (FXS), a leading known cause of inherited intellectual developmental disability. Studies have shown that CBD can reduce symptoms such as anxiety, social avoidance, hyperactivity, aggression, and sleep problems. This is a qualitative study that utilized a voluntary-anonymous survey that consisted of questions regarding demographics, medical information, the form, type, brand, dose, and frequency of CBD use, the rationale for use, the perception of effects, side effects, and costs. The full survey contained a total of 34 questions, including multiple-choice, Likert-scale, and optional free-response questions. This research revealed that there are a wide range of types, brands, and doses of CBD being administered to individuals with FXS by their parents and caregivers. There were many reasons why CBD was chosen, the most common ones being that respondents had heard positive things about CBD from members of the community, the perception that CBD had fewer side effects than other medications, and because respondents felt that CBD was a more natural substance. Most of the parents and caregivers who responded agreed that CBD improved some of the symptoms of FXS and made a positive difference overall. CBD has the therapeutic potential to help relieve some FXS symptoms. Future research is necessary to understand the benefits of CBD in FXS. Full article
(This article belongs to the Special Issue Epigenetics of Fragile X and Other Neurodevelopmental Disorders)
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13 pages, 3319 KiB  
Article
Maternal Microbiota Modulate a Fragile X-like Syndrome in Offspring Mice
by Bernard J. Varian, Katherine T. Weber, Lily J. Kim, Tony E. Chavarria, Sebastian E. Carrasco, Sureshkumar Muthupalani, Theofilos Poutahidis, Marwa Zafarullah, Reem R. Al Olaby, Mariana Barboza, Kemal Solakyildirim, Carlito Lebrilla, Flora Tassone, Fuqing Wu, Eric J. Alm and Susan E. Erdman
Genes 2022, 13(8), 1409; https://doi.org/10.3390/genes13081409 - 08 Aug 2022
Cited by 4 | Viewed by 2514
Abstract
Maternal microbial dysbiosis has been implicated in adverse postnatal health conditions in offspring, such as obesity, cancer, and neurological disorders. We observed that the progeny of mice fed a Westernized diet (WD) with low fiber and extra fat exhibited higher frequencies of stereotypy, [...] Read more.
Maternal microbial dysbiosis has been implicated in adverse postnatal health conditions in offspring, such as obesity, cancer, and neurological disorders. We observed that the progeny of mice fed a Westernized diet (WD) with low fiber and extra fat exhibited higher frequencies of stereotypy, hyperactivity, cranial features and lower FMRP protein expression, similar to what is typically observed in Fragile X Syndrome (FXS) in humans. We hypothesized that gut dysbiosis and inflammation during pregnancy influenced the prenatal uterine environment, leading to abnormal phenotypes in offspring. We found that oral in utero supplementation with a beneficial anti-inflammatory probiotic microbe, Lactobacillus reuteri, was sufficient to inhibit FXS-like phenotypes in offspring mice. Cytokine profiles in the pregnant WD females showed that their circulating levels of pro-inflammatory cytokine interleukin (Il)-17 were increased relative to matched gravid mice and to those given supplementary L. reuteri probiotic. To test our hypothesis of prenatal contributions to this neurodevelopmental phenotype, we performed Caesarian (C-section) births using dissimilar foster mothers to eliminate effects of maternal microbiota transferred during vaginal delivery or nursing after birth. We found that foster-reared offspring still displayed a high frequency of these FXS-like features, indicating significant in utero contributions. In contrast, matched foster-reared progeny of L. reuteri-treated mothers did not exhibit the FXS-like typical features, supporting a key role for microbiota during pregnancy. Our findings suggest that diet-induced dysbiosis in the prenatal uterine environment is strongly associated with the incidence of this neurological phenotype in progeny but can be alleviated by addressing gut dysbiosis through probiotic supplementation. Full article
(This article belongs to the Special Issue Epigenetics of Fragile X and Other Neurodevelopmental Disorders)
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14 pages, 1856 KiB  
Article
Differential Methylation Profile in Fragile X Syndrome-Prone Offspring Mice after in Utero Exposure to Lactobacillus Reuteri
by Reem R. AlOlaby, Marwa Zafarullah, Mariana Barboza, Gang Peng, Bernard J. Varian, Susan E. Erdman, Carlito Lebrilla and Flora Tassone
Genes 2022, 13(8), 1300; https://doi.org/10.3390/genes13081300 - 22 Jul 2022
Cited by 7 | Viewed by 3487
Abstract
Environmental factors such as diet, gut microbiota, and infections have proven to have a significant role in epigenetic modifications. It is known that epigenetic modifications may cause behavioral and neuronal changes observed in neurodevelopmental disabilities, including fragile X syndrome (FXS) and autism (ASD). [...] Read more.
Environmental factors such as diet, gut microbiota, and infections have proven to have a significant role in epigenetic modifications. It is known that epigenetic modifications may cause behavioral and neuronal changes observed in neurodevelopmental disabilities, including fragile X syndrome (FXS) and autism (ASD). Probiotics are live microorganisms that provide health benefits when consumed, and in some cases are shown to decrease the chance of developing neurological disorders. Here, we examined the epigenetic outcomes in offspring mice after feeding of a probiotic organism, Lactobacillus reuteri (L. reuteri), to pregnant mother animals. In this study, we tested a cohort of Western diet-fed descendant mice exhibiting a high frequency of behavioral features and lower FMRP protein expression similar to what is observed in FXS in humans (described in a companion manuscript in this same GENES special topic issue). By investigating 17,735 CpG sites spanning the whole mouse genome, we characterized the epigenetic profile in two cohorts of mice descended from mothers treated and non-treated with L. reuteri to determine the effect of prenatal probiotic exposure on the prevention of FXS-like symptoms. We found several genes involved in different neurological pathways being differentially methylated (p ≤ 0.05) between the cohorts. Among the key functions, synaptogenesis, neurogenesis, synaptic modulation, synaptic transmission, reelin signaling pathway, promotion of specification and maturation of neurons, and long-term potentiation were observed. The results of this study are relevant as they could lead to a better understanding of the pathways involved in these disorders, to novel therapeutics approaches, and to the identification of potential biomarkers for early detection of these conditions. Full article
(This article belongs to the Special Issue Epigenetics of Fragile X and Other Neurodevelopmental Disorders)
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9 pages, 901 KiB  
Brief Report
Expression of Transposable Elements in the Brain of the Drosophila melanogaster Model for Fragile X Syndrome
by Maria Dolores De Donno, Antonietta Puricella, Simona D’Attis, Valeria Specchia and Maria Pia Bozzetti
Genes 2023, 14(5), 1060; https://doi.org/10.3390/genes14051060 - 09 May 2023
Cited by 1 | Viewed by 1670
Abstract
Fragile X syndrome is a neuro-developmental disease affecting intellectual abilities and social interactions. Drosophila melanogaster represents a consolidated model to study neuronal pathways underlying this syndrome, especially because the model recapitulates complex behavioural phenotypes. Drosophila Fragile X protein, or FMRP, is required for [...] Read more.
Fragile X syndrome is a neuro-developmental disease affecting intellectual abilities and social interactions. Drosophila melanogaster represents a consolidated model to study neuronal pathways underlying this syndrome, especially because the model recapitulates complex behavioural phenotypes. Drosophila Fragile X protein, or FMRP, is required for a normal neuronal structure and for correct synaptic differentiation in both the peripheral and central nervous systems, as well as for synaptic connectivity during development of the neuronal circuits. At the molecular level, FMRP has a crucial role in RNA homeostasis, including a role in transposon RNA regulation in the gonads of D. m. Transposons are repetitive sequences regulated at both the transcriptional and post-transcriptional levels to avoid genomic instability. De-regulation of transposons in the brain in response to chromatin relaxation has previously been related to neurodegenerative events in Drosophila models. Here, we demonstrate for the first time that FMRP is required for transposon silencing in larval and adult brains of Drosophila “loss of function” dFmr1 mutants. This study highlights that flies kept in isolation, defined as asocial conditions, experience activation of transposable elements. In all, these results suggest a role for transposons in the pathogenesis of certain neurological alterations in Fragile X as well as in abnormal social behaviors. Full article
(This article belongs to the Special Issue Epigenetics of Fragile X and Other Neurodevelopmental Disorders)
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