Special Issue "Deciphering Epigenetic Signature in Human Health and Disease"

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

Deadline for manuscript submissions: 5 November 2021.

Special Issue Editors

Dr. Tiziana Angrisano
E-Mail Website
Guest Editor
Department of Biology, University of Naples Federico II, Monte Sant'Angelo, via Cintia 26 – 80126 Napoli, Italy
Interests: DNA methylation; chromatin dynamics; epigenetics; stem cell regulation; cancer
Dr. Michele Longo
E-Mail Website
Guest Editor
Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy
Interests: epigenetics; obesity; diabetes; insulin resistance; adipogenesis; adipose tissue dysfunction

Special Issue Information

Dear Colleagues,

Epigenetic modifications, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs, represent the regulatory network at the basis of development and differentiation. The fundamental role in gene expression puts epigenetics at the head of many diseases related to both development and cancer progression.

DNA methylation is the first mechanism that decides the fate of cells and the entire development of organisms; for this reason, aberrant methylation is a cause of altered development and is liable for tumors and several diseases. In recent years, the methylation signature has been the focus of numerous studies for the early diagnosis of diseases, given the advantage of being able to detect DNA methylation through free circulating DNA analysis. On the other hand, chromatin dynamics and the microRNA expression are directly responsible for many functions, including gene regulation, genome replication, and maintenance. The genome and epigenome in single-cell sequencing have enabled deciphering some of the epigenetic codes underlying both development and severe diseases. Today, epigenetics is still at the center of numerous studies, including those based on epigenetic drugs used for malignant phenotype reversion.

The aim of this Special Issue is to provide a broad overview of the topic of epigenetic signatures that mark development and cells differentiation. It will also discuss the correlation between epigenetics and inflammation, genetic disease, and cancer. Finally, it will give attention to the genomic distribution of DNA methylation at high resolution in various organisms, cell types, and diseases.

Dr. Tiziana Angrisano
Dr. Michele Longo
Guest Editors

Manuscript Submission Information

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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). 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

  • Epigenetics
  • DNA methylation
  • Chromatin dynamics
  • microRNA
  • Stem cell regulation
  • Epipolymorphisms
  • Epimutations
  • cfDNA
  • Epidrugs
  • Environment

Published Papers (6 papers)

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Research

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Article
Hypomethylation of AHRR (cg05575921) Is Related to Smoking Status in the Mexican Mestizo Population
Genes 2021, 12(8), 1276; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081276 - 20 Aug 2021
Viewed by 714
Abstract
Tobacco smoking results in a multifactorial disease involving environmental and genetic factors; epigenome-wide association studies (EWAS) show changes in DNA methylation levels due to cigarette consumption, partially reversible upon tobacco smoking cessation. Therefore, methylation levels could predict smoking status. This study aimed to [...] Read more.
Tobacco smoking results in a multifactorial disease involving environmental and genetic factors; epigenome-wide association studies (EWAS) show changes in DNA methylation levels due to cigarette consumption, partially reversible upon tobacco smoking cessation. Therefore, methylation levels could predict smoking status. This study aimed to evaluate the DNA methylation level of cg05575921 (AHRR) and cg23771366 (PRSS23) and their correlation with lung function variables, cigarette consumption, and nicotine addiction in the Mexican smoking population. We included 114 non-smokers (NS) and 102 current tobacco smokers (TS); we then further subclassified them as heavy smokers (HS) (n = 53) and light smokers (LS) (n = 49). We used restriction enzymes (MspI/HpaII) and qPCR to determine the DNA methylation level. We observed significant hypomethylation of cg05575921 in smokers compared to NS (p = 0.003); further analysis found a difference between HS and NS (p = 0.02). We did not observe differences between other groups or a positive correlation between methylation levels and age, BMI, cigarette consumption, nicotine addiction, or lung function. In conclusion, the cg05575921 site of AHRR is significantly hypomethylated in Mexican smokers, especially in HS (≥20 cigarettes per day). Full article
(This article belongs to the Special Issue Deciphering Epigenetic Signature in Human Health and Disease)
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Article
Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures
Genes 2021, 12(7), 1088; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071088 - 18 Jul 2021
Viewed by 641
Abstract
Dysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C (KDM5C) and its transcriptional regulators Aristaless [...] Read more.
Dysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C (KDM5C) and its transcriptional regulators Aristaless related-homeobox (ARX), PHD Finger Protein 8 (PHF8) and Zinc Finger Protein 711 (ZNF711) are functionally connected. Here, we show their relation to each other with respect to the expression levels in human and mouse datasets and in vivo mouse analysis indicating that the coexpression of these syntenic X-chromosomal genes is temporally regulated in brain areas and cellular sub-types. In co-immunoprecipitation assays, we found that the homeotic transcription factor ARX interacts with the histone demethylase PHF8, indicating that this transcriptional axis is highly intersected. Furthermore, the functional impact of pathogenic mutations of ARX, KDM5C, PHF8 and ZNF711 was tested in lymphoblastoid cell lines (LCLs) derived from children with varying levels of syndromic ID establishing the direct correlation between defects in the KDM5C-H3K4me3 pathway and ID severity. These findings reveal novel insights into epigenetic processes underpinning NDD pathogenesis and provide new avenues for assessing developmental timing and critical windows for potential treatments. Full article
(This article belongs to the Special Issue Deciphering Epigenetic Signature in Human Health and Disease)
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Article
DNA Methylation of Human Choline Kinase Alpha Promoter-Associated CpG Islands in MCF-7 Cells
Genes 2021, 12(6), 853; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060853 - 01 Jun 2021
Viewed by 807
Abstract
Choline kinase (CK) is the enzyme catalyzing the first reaction in CDP-choline pathway for the biosynthesis of phosphatidylcholine. Higher expression of the α isozyme of CK has been implicated in carcinogenesis, and inhibition or downregulation of CKα (CHKA) is a promising anticancer approach. [...] Read more.
Choline kinase (CK) is the enzyme catalyzing the first reaction in CDP-choline pathway for the biosynthesis of phosphatidylcholine. Higher expression of the α isozyme of CK has been implicated in carcinogenesis, and inhibition or downregulation of CKα (CHKA) is a promising anticancer approach. This study aimed to investigate the regulation of CKα expression by DNA methylation of the CpG islands found on the promoter of this gene in MCF-7 cells. Four CpG islands have been predicted in the 2000 bp promoter region of ckα (chka) gene. Six CpG island deletion mutants were constructed using PCR site-directed mutagenesis method and cloned into pGL4.10 vectors for promoter activity assays. Deletion of CpG4C region located between –225 and –56 significantly increased the promoter activity by 4-fold, indicating the presence of important repressive transcription factor binding site. The promoter activity of methylated full-length promoter was significantly lower than the methylated CpG4C deletion mutant by 16-fold. The results show that DNA methylation of CpG4C promotes the binding of the transcription factor that suppresses the promoter activity. Electrophoretic mobility shift assay analysis showed that cytosine methylation at MZF1 binding site in CpG4C increased the binding of putative MZF1 in nuclear extract. In conclusion, the results suggest that DNA methylation decreased the promoter activity by promoting the binding of putative MZF1 transcription factor at CpG4C region of the ckα gene promoter. Full article
(This article belongs to the Special Issue Deciphering Epigenetic Signature in Human Health and Disease)
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Article
Changes in Lactate Production, Lactate Dehydrogenase Genes Expression and DNA Methylation in Response to Tamoxifen Resistance Development in MCF-7 Cell Line
Genes 2021, 12(5), 777; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050777 - 19 May 2021
Cited by 1 | Viewed by 838
Abstract
Lactate dehydrogenase (LDH) is a key enzyme in the last step of glycolysis, playing a role in the pyruvate-to-lactate reaction. It is associated with the prognosis and metastasis of many cancers, including breast cancer. In this study, we investigated the changes in LDH [...] Read more.
Lactate dehydrogenase (LDH) is a key enzyme in the last step of glycolysis, playing a role in the pyruvate-to-lactate reaction. It is associated with the prognosis and metastasis of many cancers, including breast cancer. In this study, we investigated the changes in LDH gene expression and lactate concentrations in the culture media during tamoxifen resistance development in the MCF-7 cell line, and examined LDHB promoter methylation levels. An upregulation of 2.9 times of LDHB gene expression was observed around the IC50 concentration of tamoxifen in treated cells, while fluctuation in LDHA gene expression levels was found. Furthermore, morphological changes in the cell shape accompanied the changes in gene expression. Bisulfate treatment followed by sequencing of the LDHB promoter was performed to track any change in methylation levels; hypomethylation of CpG areas was found, suggesting that gene expression upregulation could be due to methylation level changes. Changes in LDHA and LDHB gene expression were correlated with the increase in lactate concentration in the culture media of treated MCF-7 cells. Full article
(This article belongs to the Special Issue Deciphering Epigenetic Signature in Human Health and Disease)
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Article
Association Study of SLC6A4 (5-HTTLPR) Polymorphism and Its Promoter Methylation with Rehabilitation Outcome in Patients with Subacute Stroke
Genes 2021, 12(4), 579; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040579 - 16 Apr 2021
Viewed by 511
Abstract
Recently it has been suggested that serotonin transporter (SLC6A4) and its 5HTTLPR polymorphism could be involved in post stroke recovery. Here, we characterized the methylation profile of two different CpG islands within the SLC6A4 promoter region in the whole blood of [...] Read more.
Recently it has been suggested that serotonin transporter (SLC6A4) and its 5HTTLPR polymorphism could be involved in post stroke recovery. Here, we characterized the methylation profile of two different CpG islands within the SLC6A4 promoter region in the whole blood of 50 patients with subacute stroke before and after a six-week rehabilitation treatment. These patients were genotyped for 5HTTLPR polymorphism identifying patients on the basis of short (S) and L (L) alleles: 17 patients LL, 22 patients LS and 11 patients SS. At baseline, all CpG sites for both CpG islands displayed a heterogeneous methylation percentage that were not influenced by the different genotypes. After rehabilitation, we found a significant variation in the methylation levels (increase/decrease) in the specific CpG sites of both CpG islands. The statistical analysis showed a significant relationship between the LL, LS and SS alleles and the outcome of the rehabilitation intervention (χ2 (2,50) = 6.395, p = 0.041). Specifically, we found a significant difference between patients with or without a favorable outcome in the LL (11.1% with a favorable outcome) and in the SS (54.4% with a favorable outcome) groups. Our data suggest that 5-HTTLPR polymorphisms and SLC6A4 promoter methylation may be employed as a non-invasive biological marker of recovery in patients with stroke undergoing rehabilitation. Full article
(This article belongs to the Special Issue Deciphering Epigenetic Signature in Human Health and Disease)
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Review

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Review
Epigenetic Changes Induced by Maternal Factors during Fetal Life: Implication for Type 1 Diabetes
Genes 2021, 12(6), 887; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060887 - 08 Jun 2021
Viewed by 635
Abstract
Organ-specific autoimmune diseases, such as type 1 diabetes, are believed to result from T-cell-mediated damage of the target tissue. The immune-mediated tissue injury, in turn, is known to depend on complex interactions between genetic and environmental factors. Nevertheless, the mechanisms whereby environmental factors [...] Read more.
Organ-specific autoimmune diseases, such as type 1 diabetes, are believed to result from T-cell-mediated damage of the target tissue. The immune-mediated tissue injury, in turn, is known to depend on complex interactions between genetic and environmental factors. Nevertheless, the mechanisms whereby environmental factors contribute to the pathogenesis of autoimmune diseases remain elusive and represent a major untapped target to develop novel strategies for disease prevention. Given the impact of the early environment on the developing immune system, epigenetic changes induced by maternal factors during fetal life have been linked to a likelihood of developing an autoimmune disease later in life. In humans, DNA methylation is the epigenetic mechanism most extensively investigated. This review provides an overview of the critical role of DNA methylation changes induced by prenatal maternal conditions contributing to the increased risk of immune-mediated diseases on the offspring, with a particular focus on T1D. A deeper understanding of epigenetic alterations induced by environmental stressors during fetal life may be pivotal for developing targeted prevention strategies of type 1 diabetes by modifying the maternal environment. Full article
(This article belongs to the Special Issue Deciphering Epigenetic Signature in Human Health and Disease)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Author 1

Tentative title: Association study of SLC6A4 (5-HTTLPR) polymorphism and its promoter methylation with rehabilitation outcome in patients with Subacute Stroke

Author 2

Tentative title: Analysis of syntenic X-chromosome genes implicated in neurodevelopmental diseases revealed a convergent expression profiles in human and mouse brain

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