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Epigenomics of Complex Traits and Diseases
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Epigenomics of Complex Traits and Diseases

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 33572

Special Issue Editor

Dr. Davide Gentilini

E-Mail Website1 Website2
Guest Editor
1. IRCCS Istituto Auxologico Italiano, Milan, Italy
2. Department of Brain and Behavioural Science, University of Pavia, Pavia, Italy
Interests: genomics; epigenetics; statistics; genetic epidemiology; medical statistics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genome-wide genetic information for human populations and phenotypes is becoming increasingly abundant because of the efforts of genomes sequencing projects and the recent wave of genome-wide association studies (GWASs) in human complex traits. Thousands of genetic variants have been associated with diseases and complex traits, with very good estimates of the effect size and the significance of the effects. While this is a major milestone in human genetics, these studies generally failed in their primary intent. Despite the hundreds of millions of dollars spent on genome-wide association studies, most of the genetic variance in the risks for the most common diseases remains undiscovered. Recent advances in genomic technologies have placed us in a position to initiate large-scale studies of human disease-associated epigenetic variation, specifically variations in DNA methylation. Epigenetics appears to be an interesting opportunity to shed light on the genomic contribution in the field of complex traits and diseases.

Topics of this Special Issue include, but are not limited to, the following:

  • Genetic and epigenetic variability of complex traits and diseases
  • Genetics and epigenetics of aging
  • Epigenetics modification in cancer
  • Epigenomic-wide association studies in the field of complex traits and diseases
  • Methodological approaches for the integration of omic data

Dr. Davide Gentilini
Guest Editor

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Keywords

  • Complex traits
  • EWAS
  • Epigenomics
  • DNA methylation
  • Complex diseases
  • Next generation sequencing
  • Histone modifications
  • Aging
  • Cancer
  • Common diseases

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Published Papers (6 papers)

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Research

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19 pages, 2475 KiB  
Article
Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS)
by Valentina Guida, Luciano Calzari, Maria Teresa Fadda, Francesca Piceci-Sparascio, Maria Cristina Digilio, Laura Bernardini, Francesco Brancati, Teresa Mattina, Daniela Melis, Francesca Forzano, Silvana Briuglia, Tommaso Mazza, Sebastiano Bianca, Enza Maria Valente, Leila Bagherjad Salehi, Paolo Prontera, Mario Pagnoni, Romano Tenconi, Bruno Dallapiccola, Giorgio Iannetti, Luigi Corsaro, Alessandro De Luca and Davide Gentiliniadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(3), 1190; https://doi.org/10.3390/ijms22031190 - 26 Jan 2021
Cited by 16 | Viewed by 4144
Abstract
Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, [...] Read more.
Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, and ZYG11B gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder. Full article
(This article belongs to the Special Issue Epigenomics of Complex Traits and Diseases)
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25 pages, 4300 KiB  
Article
A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients
by Luca Bedon, Michele Dal Bo, Monica Mossenta, Davide Busato, Giuseppe Toffoli and Maurizio Polano
Int. J. Mol. Sci. 2021, 22(3), 1075; https://doi.org/10.3390/ijms22031075 - 22 Jan 2021
Cited by 6 | Viewed by 3770
Abstract
Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define [...] Read more.
Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment. Full article
(This article belongs to the Special Issue Epigenomics of Complex Traits and Diseases)
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14 pages, 2051 KiB  
Article
Epigenome Wide Association and Stochastic Epigenetic Mutation Analysis on Cord Blood of Preterm Birth
by Elena Spada, Luciano Calzari, Luigi Corsaro, Teresa Fazia, Monica Mencarelli, Anna Maria Di Blasio, Luisa Bernardinelli, Giulia Zangheri, Michele Vignali and Davide Gentilini
Int. J. Mol. Sci. 2020, 21(14), 5044; https://doi.org/10.3390/ijms21145044 - 17 Jul 2020
Cited by 15 | Viewed by 3246
Abstract
Preterm birth (PTB) can be defined as the endpoint of a complex process that could be influenced by maternal and environmental factors. Epigenetics recently emerged as an interesting field of investigation since it represents an important mechanism of regulation. This study evaluates epigenetic [...] Read more.
Preterm birth (PTB) can be defined as the endpoint of a complex process that could be influenced by maternal and environmental factors. Epigenetics recently emerged as an interesting field of investigation since it represents an important mechanism of regulation. This study evaluates epigenetic impact of preterm birth on DNA methylation. Genome-wide DNAm was measured using the Illumina 450K array in cord blood samples obtained from 72 full term and 18 preterm newborns. Lymphocyte composition was calculated based on specific epigenetic markers that are present on the 450k array. Differential methylation analysis was performed both at site and region level; moreover, stochastic epigenetic mutations (SEMs) were also evaluated. The study showed significant differences in blood cell composition between the two groups. Moreover, after multiple testing correction, statistically significant differences in DNA methylation levels emerged between the two groups both at site and region levels. Results obtained were compared to those reported by previous EWAS, leading to a list of more consistent genes associated with PTB. Finally, the SEMs analysis revealed that the burden of SEMs resulted significantly higher in the preterm group. In conclusion, PTB resulted associated to specific epigenetic signatures that involve immune system. Moreover, SEMs analysis revealed an increased epigenetic drift at birth in the preterm group. Full article
(This article belongs to the Special Issue Epigenomics of Complex Traits and Diseases)
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16 pages, 3698 KiB  
Article
Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression
by Ana Florencia Vega-Benedetti, Eleonora Loi, Loredana Moi, Sandra Orrù, Pina Ziranu, Andrea Pretta, Eleonora Lai, Marco Puzzoni, Letizia Ciccone, Andrea Casadei-Gardini, Francesco Cabras, Federica Fortunato, Angelo Restivo, Luigi Zorcolo, Mario Scartozzi and Patrizia Zavattari
Int. J. Mol. Sci. 2020, 21(12), 4494; https://doi.org/10.3390/ijms21124494 - 24 Jun 2020
Cited by 25 | Viewed by 3502
Abstract
Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis [...] Read more.
Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis through non-invasive methods. In our previous work, we identified 74 early altered CpG islands (CGIs) associated with genes involved in cell cross-talking and cell signalling pathways. The aim of this work was to test whether methylation-based biomarkers could be detected in non-invasive matrices. Our results confirmed methylation alterations of GRIA4 and VIPR2 in CRC tissues, using MethyLight, as well as in stool samples, using a much more sensitive technique as droplet digital PCR. Furthermore, we analysed expression levels of selected genes whose promoter CGIs were hypermethylated in CRC, detecting downregulation at mRNA and protein levels in CRC tissue for GRIA4, VIPR2, SPOCK1 and SLC6A3. Most of these genes were already lowly expressed in colon normal tissues supporting the idea that cancer DNA methylation targets genes already barely expressed in the matched normal tissues. Our study suggests GRIA4 and VIPR2 as biomarkers for early CRC diagnosis using stool samples and confirms downregulation of genes hypermethylated in CRC. Full article
(This article belongs to the Special Issue Epigenomics of Complex Traits and Diseases)
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Review

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31 pages, 1737 KiB  
Review
Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy
by Aintzane Urbizu and Katrin Beyer
Int. J. Mol. Sci. 2020, 21(13), 4718; https://doi.org/10.3390/ijms21134718 - 2 Jul 2020
Cited by 16 | Viewed by 4281
Abstract
Lewy body disorders (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and [...] Read more.
Lewy body disorders (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research. Full article
(This article belongs to the Special Issue Epigenomics of Complex Traits and Diseases)
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12 pages, 505 KiB  
Review
Pathogenomics of Uterine Fibroids Development
by Vladislav S. Baranov, Natalia S. Osinovskaya and Maria I. Yarmolinskaya
Int. J. Mol. Sci. 2019, 20(24), 6151; https://doi.org/10.3390/ijms20246151 - 6 Dec 2019
Cited by 49 | Viewed by 13923
Abstract
We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)—a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, [...] Read more.
We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)—a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease. Full article
(This article belongs to the Special Issue Epigenomics of Complex Traits and Diseases)
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