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Epigenetic Mechanisms and Human Pathology 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 75012

Special Issue Editors

Dr. Pawel Karpinski

E-Mail Website
Guest Editor
Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland
Interests: epigenetics; bioinformatics; cancer microenvironment; cancer immunology; tumor subtyping
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maria M. Sasiadek

E-Mail Website
Guest Editor
Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland
Interests: DNA methylation; epigenetics; protein tyrosine phosphatases; tyrosine receptor; dephosphorylation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second volume of our previous Special Issue "Epigenetic Mechanisms and Human Pathology". Growing evidence indicates that addressing the direct effects of genetic and environmental factors might be insufficient to understand the mechanisms underlying the complexity of human pathologies. The recognition of epigenetic mechanisms has largely improved our understanding of human diseases. The term "epigenetics" refers to several molecular mechanisms that impact DNA expression without altering its sequence. Epigenetic regulation of gene expression includes three main mechanisms, i.e., DNA methylation, histone modifications, and non-protein-coding RNAs (npcRNAs), which play a fundamental role in all molecular processes in living organisms. Consequently, any alterations in these mechanisms may result in a whole range of human pathologies including pediatric, psychiatric, neurologic, endocrine disorders, as well as cancer and non-communicable chronic adulthood diseases. The mostly reversible nature of epigenetic alterations provides grounds for developing novel treatment targets and personalized therapies.

This Special Issue of the International Journal of Molecular Sciences entitled: “Epigenetic Mechanisms and Human Pathology” shall serve as a forum to present state-of-the-art and critical reviews, as well as original papers discussing the application of epigenetic approaches to the etiology, diagnostics, and therapy of a variety of diseases.

Contributions from leading international investigators will guarantee a broad and comprehensive analysis of potential epigenetic mechanisms as well as related clinical problems.

Dr. Pawel Karpinski
Prof. Dr. Maria M. Sasiadek
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • human pathology
  • cancer
  • DNA methylation
  • npcRNA, histone modification
  • personalized therapy

Published Papers (20 papers)

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Research

Jump to: Review

12 pages, 1463 KiB  
Article
Global DNA Methylation Profiling Reveals Differentially Methylated CpGs between Salivary Gland Pleomorphic Adenomas with Distinct Clinical Course
by Katarzyna Kiwerska, Ewelina Kowal-Wisniewska, Adam Ustaszewski, Ewelina Bartkowiak, Malgorzata Jarmuz-Szymczak, Malgorzata Wierzbicka and Maciej Giefing
Int. J. Mol. Sci. 2022, 23(11), 5962; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115962 - 25 May 2022
Cited by 2 | Viewed by 1624
Abstract
Pleomorphic adenomas (PAs) are the most frequently diagnosed benign salivary gland tumors. Although the majority of PAs are characterized by slow growth, some develop very fast and are more prone to recur. The reason for such differences remains unidentified. In this study, we [...] Read more.
Pleomorphic adenomas (PAs) are the most frequently diagnosed benign salivary gland tumors. Although the majority of PAs are characterized by slow growth, some develop very fast and are more prone to recur. The reason for such differences remains unidentified. In this study, we performed global DNA methylation profiling using the Infinium Human Methylation EPIC 850k BeadChip Array (Illumina) to search for epigenetic biomarkers that could distinguish both groups of tumors. The analysis was performed in four fast-growing tumors (FGTs) and four slow-growing tumors (SGTs). In all, 85 CpG dinucleotides differentiating both groups were identified. Six CpG tags (cg06748470, cg18413218, cg10121788, cg08249296, cg18455472, and cg19930657) were selected for bisulfite pyrosequencing in the extended group of samples. We confirmed differences in DNA methylation between both groups of samples. To evaluate the potential diagnostic accuracy of the selected markers, ROC curves were constructed. We indicated that CpGs included in two assays showed an area under the curve with an acceptable prognostic value (AUC > 0.7). However, logistic regression analysis allowed us to indicate a more optimal model consisting of five CpGs ((1) cg06748470, (2) cg00600454, (3) CpG located in chr14: 77,371,501–77,371,502 (not annotated in GRCh37/hg19), (4) CpG2 located in chr16: 77,469,589–77,469,590 (not annotated GRCh37/hg19), and (5) cg19930657) with AUC > 0.8. This set of epigenetic biomarkers may be considered as differentiating factors between FGT and SGT during salivary gland tumor diagnosis. However, this data should be confirmed in a larger cohort of samples. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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12 pages, 1500 KiB  
Article
MicroRNA-20a-5p Downregulation by Atorvastatin: A Potential Mechanism Involved in Lipid-Lowering Therapy
by Kathleen Saavedra, Karla Leal, Nicolás Saavedra, Yalena Prado, Isis Paez, Carmen G. Ubilla, Gabriel Rojas and Luis A. Salazar
Int. J. Mol. Sci. 2022, 23(9), 5022; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095022 - 30 Apr 2022
Cited by 2 | Viewed by 1734
Abstract
The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the [...] Read more.
The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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20 pages, 5289 KiB  
Article
Long Non-Coding RNAs Might Regulate Phenotypic Switch of Vascular Smooth Muscle Cells Acting as ceRNA: Implications for In-Stent Restenosis
by Alberto Arencibia, Fernando Lanas and Luis A. Salazar
Int. J. Mol. Sci. 2022, 23(6), 3074; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063074 - 12 Mar 2022
Cited by 3 | Viewed by 2473
Abstract
Coronary in-stent restenosis is a late complication of angioplasty. It is a multifactorial process that involves vascular smooth muscle cells (VSMCs), endothelial cells, and inflammatory and genetic factors. In this study, the transcriptomic landscape of VSMCs’ phenotypic switch process was assessed under stimuli [...] Read more.
Coronary in-stent restenosis is a late complication of angioplasty. It is a multifactorial process that involves vascular smooth muscle cells (VSMCs), endothelial cells, and inflammatory and genetic factors. In this study, the transcriptomic landscape of VSMCs’ phenotypic switch process was assessed under stimuli resembling stent injury. Co-cultured contractile VSMCs and endothelial cells were exposed to a bare metal stent and platelet-derived growth factor (PDGF-BB) 20 ng/mL. Migratory capacity (wound healing assay), proliferative capacity, and cell cycle analysis of the VSMCs were performed. RNAseq analysis of contractile vs. proliferative VSMCs was performed. Gene differential expression (DE), identification of new long non-coding RNA candidates (lncRNAs), gene ontology (GO), and pathway enrichment (KEGG) were analyzed. A competing endogenous RNA network was constructed, and significant lncRNA–miRNA–mRNA axes were selected. VSMCs exposed to “stent injury” conditions showed morphologic changes, with proliferative and migratory capacities progressing from G0-G1 cell cycle phase to S and G2-M. RNAseq analysis showed DE of 1099, 509 and 64 differentially expressed mRNAs, lncRNAs, and miRNAs, respectively. GO analysis of DE genes showed significant enrichment in collagen and extracellular matrix organization, regulation of smooth muscle cell proliferation, and collagen biosynthetic process. The main upregulated nodes in the lncRNA-mediated ceRNA network were PVT1 and HIF1-AS2, with downregulation of ACTA2-AS1 and MIR663AHG. The PVT1 ceRNA axis appears to be an attractive target for in-stent restenosis diagnosis and treatment. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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15 pages, 2129 KiB  
Article
The HDAC Inhibitor Butyrate Impairs β Cell Function and Activates the Disallowed Gene Hexokinase I
by Stephanie Bridgeman, Gaewyn Ellison, Philip Newsholme and Cyril Mamotte
Int. J. Mol. Sci. 2021, 22(24), 13330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413330 - 11 Dec 2021
Cited by 11 | Viewed by 2528
Abstract
Histone deacetylase (HDAC) inhibitors such as butyrate have been reported to reduce diabetes risk and protect insulin-secreting pancreatic β cells in animal models. However, studies on insulin-secreting cells in vitro have found that butyrate treatment resulted in impaired or inappropriate insulin secretion. Our [...] Read more.
Histone deacetylase (HDAC) inhibitors such as butyrate have been reported to reduce diabetes risk and protect insulin-secreting pancreatic β cells in animal models. However, studies on insulin-secreting cells in vitro have found that butyrate treatment resulted in impaired or inappropriate insulin secretion. Our study explores the effects of butyrate on insulin secretion by BRIN BD-11 rat pancreatic β cells and examined effects on the expression of genes implicated in β cell function. Robust HDAC inhibition with 5 mM butyrate or trichostatin A for 24 h in β cells decreased basal insulin secretion and content, as well as insulin secretion in response to acute stimulation. Treatment with butyrate also increased expression of the disallowed gene hexokinase I, possibly explaining the impairment to insulin secretion, and of TXNIP, which may increase oxidative stress and β cell apoptosis. In contrast to robust HDAC inhibition (>70% after 24 h), low-dose and acute high-dose treatment with butyrate enhanced nutrient-stimulated insulin secretion. In conclusion, although protective effects of HDAC inhibition have been observed in vivo, potent HDAC inhibition impairs β cell function in vitro. The chronic low dose and acute high dose butyrate treatments may be more reflective of in vivo effects. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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25 pages, 1958 KiB  
Article
Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression
by Ann-Kathrin Eichelmann, George C. Mayne, Karen Chiam, Steven L. Due, Isabell Bastian, Frederike Butz, Tingting Wang, Pamela J. Sykes, Nicholas J. Clemons, David S. Liu, Michael Z. Michael, Christos S. Karapetis, Richard Hummel, David I. Watson and Damian J. Hussey
Int. J. Mol. Sci. 2021, 22(11), 5547; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115547 - 24 May 2021
Cited by 8 | Viewed by 3225
Abstract
TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy [...] Read more.
TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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Review

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36 pages, 1202 KiB  
Review
Epigenetic and Genetic Factors Related to Curve Progression in Adolescent Idiopathic Scoliosis: A Systematic Scoping Review of the Current Literature
by Cesare Faldini, Marco Manzetti, Simona Neri, Francesca Barile, Giovanni Viroli, Giuseppe Geraci, Francesco Ursini and Alberto Ruffilli
Int. J. Mol. Sci. 2022, 23(11), 5914; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115914 - 25 May 2022
Cited by 14 | Viewed by 5450
Abstract
Adolescent idiopathic scoliosis (AIS) is a progressive deformity of the spine. Scoliotic curves progress until skeletal maturity leading, in rare cases, to a severe deformity. While the Cobb angle is a straightforward tool in initial curve magnitude measurement, assessing the risk of curve [...] Read more.
Adolescent idiopathic scoliosis (AIS) is a progressive deformity of the spine. Scoliotic curves progress until skeletal maturity leading, in rare cases, to a severe deformity. While the Cobb angle is a straightforward tool in initial curve magnitude measurement, assessing the risk of curve progression at the time of diagnosis may be more challenging. Epigenetic and genetic markers are potential prognostic tools to predict curve progression. The aim of this study is to review the available literature regarding the epigenetic and genetic factors associated with the risk of AIS curve progression. This review was carried out in accordance with Preferential Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The search was carried out in January 2022. Only peer-reviewed articles were considered for inclusion. Forty studies were included; fifteen genes were reported as having SNPs with significant association with progressive AIS, but none showed sufficient power to sustain clinical applications. In contrast, nine studies reporting epigenetic modifications showed promising results in terms of reliable markers. Prognostic testing for AIS has the potential to significantly modify disease management. Most recent evidence suggests epigenetics as a more promising field for the identification of factors associated with AIS progression, offering a rationale for further investigation in this field. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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18 pages, 2340 KiB  
Review
Challenges in Analyzing Functional Epigenetic Data in Perspective of Adolescent Psychiatric Health
by Diana M. Manu, Jessica Mwinyi and Helgi B. Schiöth
Int. J. Mol. Sci. 2022, 23(10), 5856; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105856 - 23 May 2022
Viewed by 2459
Abstract
The formative period of adolescence plays a crucial role in the development of skills and abilities for adulthood. Adolescents who are affected by mental health conditions are at risk of suicide and social and academic impairments. Gene–environment complementary contributions to the molecular mechanisms [...] Read more.
The formative period of adolescence plays a crucial role in the development of skills and abilities for adulthood. Adolescents who are affected by mental health conditions are at risk of suicide and social and academic impairments. Gene–environment complementary contributions to the molecular mechanisms involved in psychiatric disorders have emphasized the need to analyze epigenetic marks such as DNA methylation (DNAm) and non-coding RNAs. However, the large and diverse bioinformatic and statistical methods, referring to the confounders of the statistical models, application of multiple-testing adjustment methods, questions regarding the correlation of DNAm across tissues, and sex-dependent differences in results, have raised challenges regarding the interpretation of the results. Based on the example of generalized anxiety disorder (GAD) and depressive disorder (MDD), we shed light on the current knowledge and usage of methodological tools in analyzing epigenetics. Statistical robustness is an essential prerequisite for a better understanding and interpretation of epigenetic modifications and helps to find novel targets for personalized therapeutics in psychiatric diseases. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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26 pages, 1035 KiB  
Review
DNA Hydroxymethylation in Smoking-Associated Cancers
by Ahmad Besaratinia, Amanda Caceres and Stella Tommasi
Int. J. Mol. Sci. 2022, 23(5), 2657; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052657 - 28 Feb 2022
Cited by 7 | Viewed by 4145
Abstract
5-hydroxymethylcytosine (5-hmC) was first detected in mammalian DNA five decades ago. However, it did not take center stage in the field of epigenetics until 2009, when ten-eleven translocation 1 (TET1) was found to oxidize 5-methylcytosine to 5-hmC, thus offering a long-awaited mechanism for [...] Read more.
5-hydroxymethylcytosine (5-hmC) was first detected in mammalian DNA five decades ago. However, it did not take center stage in the field of epigenetics until 2009, when ten-eleven translocation 1 (TET1) was found to oxidize 5-methylcytosine to 5-hmC, thus offering a long-awaited mechanism for active DNA demethylation. Since then, a remarkable body of research has implicated DNA hydroxymethylation in pluripotency, differentiation, neural system development, aging, and pathogenesis of numerous diseases, especially cancer. Here, we focus on DNA hydroxymethylation in smoking-associated carcinogenesis to highlight the diagnostic, therapeutic, and prognostic potentials of this epigenetic mark. We describe the significance of 5-hmC in DNA demethylation, the importance of substrates and cofactors in TET-mediated DNA hydroxymethylation, the regulation of TETs and related genes (isocitrate dehydrogenases, fumarate hydratase, and succinate dehydrogenase), the cell-type dependency and genomic distribution of 5-hmC, and the functional role of 5-hmC in the epigenetic regulation of transcription. We showcase examples of studies on three major smoking-associated cancers, including lung, bladder, and colorectal cancers, to summarize the current state of knowledge, outstanding questions, and future direction in the field. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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18 pages, 1330 KiB  
Review
The Current State of Chromatin Immunoprecipitation (ChIP) from FFPE Tissues
by Stefano Amatori and Mirco Fanelli
Int. J. Mol. Sci. 2022, 23(3), 1103; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031103 - 20 Jan 2022
Cited by 6 | Viewed by 3506
Abstract
Cancer cells accumulate epigenomic aberrations that contribute to cancer initiation and progression by altering both the genomic stability and the expression of genes. The awareness of such alterations could improve our understanding of cancer dynamics and the identification of new therapeutic strategies and [...] Read more.
Cancer cells accumulate epigenomic aberrations that contribute to cancer initiation and progression by altering both the genomic stability and the expression of genes. The awareness of such alterations could improve our understanding of cancer dynamics and the identification of new therapeutic strategies and biomarkers to refine tumor classification and treatment. Formalin fixation and paraffin embedding (FFPE) is the gold standard to preserve both tissue integrity and organization, and, in the last decades, a huge number of biological samples have been archived all over the world following this procedure. Recently, new chromatin immunoprecipitation (ChIP) techniques have been developed to allow the analysis of histone post-translational modifications (PTMs) and transcription factor (TF) distribution in FFPE tissues. The application of ChIP to genome-wide chromatin studies using real archival samples represents an unprecedented opportunity to conduct retrospective clinical studies thanks to the possibility of accessing large cohorts of samples and their associated diagnostic records. However, although recent attempts to standardize have been made, fixation and storage conditions of clinical specimens are still extremely variable and can affect the success of chromatin studies. The procedures introduced in the last few years dealt with this problem proponing successful strategies to obtain high-resolution ChIP profiles from FFPE archival samples. In this review, we compare the different FFPE-ChIP techniques, highlighting their strengths, limitations, common features, and peculiarities, as well as pitfalls and caveats related to ChIP studies in FFPE samples, in order to facilitate their application. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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21 pages, 2745 KiB  
Review
CpG Island Methylator Phenotype—A Hope for the Future or a Road to Nowhere?
by Karpiński Paweł and Sąsiadek Maria Małgorzata
Int. J. Mol. Sci. 2022, 23(2), 830; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020830 - 13 Jan 2022
Cited by 7 | Viewed by 2637
Abstract
The CpG island methylator phenotype (CIMP) can be regarded as the most notable emanation of epigenetic instability in cancer. Since its discovery in the late 1990s, CIMP has been extensively studied, mainly in colorectal cancers (CRC) and gliomas. Consequently, knowledge on molecular and [...] Read more.
The CpG island methylator phenotype (CIMP) can be regarded as the most notable emanation of epigenetic instability in cancer. Since its discovery in the late 1990s, CIMP has been extensively studied, mainly in colorectal cancers (CRC) and gliomas. Consequently, knowledge on molecular and pathological characteristics of CIMP in CRC and other tumour types has rapidly expanded. Concordant and widespread hypermethylation of multiple CpG islands observed in CIMP in multiple cancers raised hopes for future epigenetically based diagnostics and treatments of solid tumours. However, studies on CIMP in solid tumours were hampered by a lack of generalisability and reproducibility of epigenetic markers. Moreover, CIMP was not a satisfactory marker in predicting clinical outcomes. The idea of targeting epigenetic abnormalities such as CIMP for cancer therapy has not been implemented for solid tumours, either. Twenty-one years after its discovery, we aim to cover both the fundamental and new aspects of CIMP and its future application as a diagnostic marker and target in anticancer therapies. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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20 pages, 18614 KiB  
Review
Epigenetic Mechanisms in Parenchymal Lung Diseases: Bystanders or Therapeutic Targets?
by Edibe Avci, Pouya Sarvari, Rajkumar Savai, Werner Seeger and Soni S. Pullamsetti
Int. J. Mol. Sci. 2022, 23(1), 546; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010546 - 04 Jan 2022
Cited by 10 | Viewed by 6782
Abstract
Epigenetic responses due to environmental changes alter chromatin structure, which in turn modifies the phenotype, gene expression profile, and activity of each cell type that has a role in the pathophysiology of a disease. Pulmonary diseases are one of the major causes of [...] Read more.
Epigenetic responses due to environmental changes alter chromatin structure, which in turn modifies the phenotype, gene expression profile, and activity of each cell type that has a role in the pathophysiology of a disease. Pulmonary diseases are one of the major causes of death in the world, including lung cancer, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung tuberculosis, pulmonary embolism, and asthma. Several lines of evidence indicate that epigenetic modifications may be one of the main factors to explain the increasing incidence and prevalence of lung diseases including IPF and COPD. Interestingly, isolated fibroblasts and smooth muscle cells from patients with pulmonary diseases such as IPF and PH that were cultured ex vivo maintained the disease phenotype. The cells often show a hyper-proliferative, apoptosis-resistant phenotype with increased expression of extracellular matrix (ECM) and activated focal adhesions suggesting the presence of an epigenetically imprinted phenotype. Moreover, many abnormalities observed in molecular processes in IPF patients are shown to be epigenetically regulated, such as innate immunity, cellular senescence, and apoptotic cell death. DNA methylation, histone modification, and microRNA regulation constitute the most common epigenetic modification mechanisms. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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17 pages, 1956 KiB  
Review
The Regulation of Collagen Processing by miRNAs in Disease and Possible Implications for Bone Turnover
by Tomasz P. Lehmann, Urszula Guderska, Klaudia Kałek, Maria Marzec, Agnieszka Urbanek, Alicja Czernikiewicz, Maria Sąsiadek, Paweł Karpiński, Andrzej Pławski, Maciej Głowacki and Paweł P. Jagodziński
Int. J. Mol. Sci. 2022, 23(1), 91; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010091 - 22 Dec 2021
Cited by 3 | Viewed by 2929
Abstract
This article describes several recent examples of miRNA governing the regulation of the gene expression involved in bone matrix construction. We present the impact of miRNA on the subsequent steps in the formation of collagen type I. Collagen type I is a main [...] Read more.
This article describes several recent examples of miRNA governing the regulation of the gene expression involved in bone matrix construction. We present the impact of miRNA on the subsequent steps in the formation of collagen type I. Collagen type I is a main factor of mechanical bone stiffness because it constitutes 90–95% of the organic components of the bone. Therefore, the precise epigenetic regulation of collagen formation may have a significant influence on bone structure. We also describe miRNA involvement in the expression of genes, the protein products of which participate in collagen maturation in various tissues and cancer cells. We show how non-collagenous proteins in the extracellular matrix are epigenetically regulated by miRNA in bone and other tissues. We also delineate collagen mineralisation in bones by factors that depend on miRNA molecules. This review reveals the tissue variability of miRNA regulation at different levels of collagen maturation and mineralisation. The functionality of collagen mRNA regulation by miRNA, as proven in other tissues, has not yet been shown in osteoblasts. Several collagen-regulating miRNAs are co-expressed with collagen in bone. We suggest that collagen mRNA regulation by miRNA could also be potentially important in bone metabolism. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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12 pages, 543 KiB  
Review
Recent Discoveries in Epigenetic Modifications of Polycystic Kidney Disease
by Sarah A. Bowden, Euan J. Rodger, Aniruddha Chatterjee, Michael R. Eccles and Cherie Stayner
Int. J. Mol. Sci. 2021, 22(24), 13327; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413327 - 11 Dec 2021
Cited by 8 | Viewed by 3509
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a heritable renal disease that results in end-stage kidney disease, due to the uncontrolled bilateral growth of cysts throughout the kidneys. While it is known that a mutation within a PKD-causing gene is required for the [...] Read more.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a heritable renal disease that results in end-stage kidney disease, due to the uncontrolled bilateral growth of cysts throughout the kidneys. While it is known that a mutation within a PKD-causing gene is required for the development of ADPKD, the underlying mechanism(s) causing cystogenesis and progression of the disease are not well understood. Limited therapeutic options are currently available to slow the rate of cystic growth. Epigenetic modifications, including DNA methylation, are known to be altered in neoplasia, and several FDA-approved therapeutics target these disease-specific changes. As there are many similarities between ADPKD and neoplasia, we (and others) have postulated that ADPKD kidneys contain alterations to their epigenetic landscape that could be exploited for future therapeutic discovery. Here we summarise the current understanding of epigenetic changes that are associated with ADPKD, with a particular focus on the burgeoning field of ADPKD-specific alterations in DNA methylation. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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16 pages, 1330 KiB  
Review
Physical Activity and DNA Methylation in Humans
by Witold Józef Światowy, Hanna Drzewiecka, Michalina Kliber, Maria Sąsiadek, Paweł Karpiński, Andrzej Pławski and Paweł Piotr Jagodziński
Int. J. Mol. Sci. 2021, 22(23), 12989; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312989 - 30 Nov 2021
Cited by 29 | Viewed by 4011
Abstract
Physical activity is a strong stimulus influencing the overall physiology of the human body. Exercises lead to biochemical changes in various tissues and exert an impact on gene expression. Exercise-induced changes in gene expression may be mediated by epigenetic modifications, which rearrange the [...] Read more.
Physical activity is a strong stimulus influencing the overall physiology of the human body. Exercises lead to biochemical changes in various tissues and exert an impact on gene expression. Exercise-induced changes in gene expression may be mediated by epigenetic modifications, which rearrange the chromatin structure and therefore modulate its accessibility for transcription factors. One of such epigenetic mark is DNA methylation that involves an attachment of a methyl group to the fifth carbon of cytosine residue present in CG dinucleotides (CpG). DNA methylation is catalyzed by a family of DNA methyltransferases. This reversible DNA modification results in the recruitment of proteins containing methyl binding domain and further transcriptional co-repressors leading to the silencing of gene expression. The accumulation of CpG dinucleotides, referred as CpG islands, occurs at the promoter regions in a great majority of human genes. Therefore, changes in DNA methylation profile affect the transcription of multiple genes. A growing body of evidence indicates that exercise training modulates DNA methylation in muscles and adipose tissue. Some of these epigenetic markers were associated with a reduced risk of chronic diseases. This review summarizes the current knowledge about the influence of physical activity on the DNA methylation status in humans. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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24 pages, 809 KiB  
Review
Dysregulated MicroRNAs as Biomarkers or Therapeutic Targets in Cisplatin-Induced Nephrotoxicity: A Systematic Review
by Nadine de Godoy Torso, João Kleber Novais Pereira, Marília Berlofa Visacri, Pedro Eduardo Nascimento Silva Vasconcelos, Pía Loren, Kathleen Saavedra, Nicolás Saavedra, Luis A. Salazar and Patricia Moriel
Int. J. Mol. Sci. 2021, 22(23), 12765; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312765 - 25 Nov 2021
Cited by 6 | Viewed by 2358
Abstract
The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in [...] Read more.
The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in silico analysis of the two miRNAs found to be dysregulated in the majority of studies was performed. A literature search was performed using eight databases for studies published up to 4 July 2021. Two independent reviewers selected the studies and extracted the data; disagreements were resolved by a third and fourth reviewers. A total of 1002 records were identified, of which 30 met the eligibility criteria. All studies were published in English and reported between 2010 and 2021. The main findings were as follows: (a) miR-34a and miR-21 were the main miRNAs identified by the studies as possible biomarkers and therapeutic targets of cisplatin nephrotoxicity; (b) the in silico analysis revealed 124 and 131 different strongly validated targets for miR-34a and miR-21, respectively; and (c) studies in humans remain scarce. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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18 pages, 1298 KiB  
Review
Epigenetics of Myotonic Dystrophies: A Minireview
by Virginia Veronica Visconti, Federica Centofanti, Simona Fittipaldi, Elisa Macrì, Giuseppe Novelli and Annalisa Botta
Int. J. Mol. Sci. 2021, 22(22), 12594; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212594 - 22 Nov 2021
Cited by 8 | Viewed by 4085
Abstract
Myotonic dystrophy type 1 and 2 (DM1 and DM2) are two multisystemic autosomal dominant disorders with clinical and genetic similarities. The prevailing paradigm for DMs is that they are mediated by an in trans toxic RNA mechanism, triggered by untranslated CTG and CCTG [...] Read more.
Myotonic dystrophy type 1 and 2 (DM1 and DM2) are two multisystemic autosomal dominant disorders with clinical and genetic similarities. The prevailing paradigm for DMs is that they are mediated by an in trans toxic RNA mechanism, triggered by untranslated CTG and CCTG repeat expansions in the DMPK and CNBP genes for DM1 and DM2, respectively. Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of both diseases. In this review, we discuss the available information on epigenetic mechanisms that could contribute to the DMs outcome and progression. Changes in DNA cytosine methylation, chromatin remodeling and expression of regulatory noncoding RNAs are described, with the intent of depicting an epigenetic signature of DMs. Epigenetic biomarkers have a strong potential for clinical application since they could be used as targets for therapeutic interventions avoiding changes in DNA sequences. Moreover, understanding their clinical significance may serve as a diagnostic indicator in genetic counselling in order to improve genotype–phenotype correlations in DM patients. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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20 pages, 1410 KiB  
Review
The Impact of Epigenetic Modifications on Adaptive Resistance Evolution in Glioblastoma
by Qiong Wu, Anders E. Berglund and Arnold B. Etame
Int. J. Mol. Sci. 2021, 22(15), 8324; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158324 - 03 Aug 2021
Cited by 14 | Viewed by 3088
Abstract
Glioblastoma (GBM) is a highly lethal cancer that is universally refractory to the standard multimodal therapies of surgical resection, radiation, and chemotherapy treatment. Temozolomide (TMZ) is currently the best chemotherapy agent for GBM, but the durability of response is epigenetically dependent and often [...] Read more.
Glioblastoma (GBM) is a highly lethal cancer that is universally refractory to the standard multimodal therapies of surgical resection, radiation, and chemotherapy treatment. Temozolomide (TMZ) is currently the best chemotherapy agent for GBM, but the durability of response is epigenetically dependent and often short-lived secondary to tumor resistance. Therapies that can provide synergy to chemoradiation are desperately needed in GBM. There is accumulating evidence that adaptive resistance evolution in GBM is facilitated through treatment-induced epigenetic modifications. Epigenetic alterations of DNA methylation, histone modifications, and chromatin remodeling have all been implicated as mechanisms that enhance accessibility for transcriptional activation of genes that play critical roles in GBM resistance and lethality. Hence, understanding and targeting epigenetic modifications associated with GBM resistance is of utmost priority. In this review, we summarize the latest updates on the impact of epigenetic modifications on adaptive resistance evolution in GBM to therapy. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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17 pages, 485 KiB  
Review
Epigenetic Modifications Associated with Exposure to Endocrine Disrupting Chemicals in Patients with Gestational Diabetes Mellitus
by Mateusz Kunysz, Olimpia Mora-Janiszewska and Dorota Darmochwał-Kolarz
Int. J. Mol. Sci. 2021, 22(9), 4693; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094693 - 29 Apr 2021
Cited by 16 | Viewed by 3234
Abstract
Gestational diabetes mellitus (GDM) remains a significant clinical and public health issue due to its increasing prevalence and the possibility for numerous short- and long-term complications. The growing incidence of GDM seems to coincide with the widespread use of endocrine disrupting chemicals (EDCs). [...] Read more.
Gestational diabetes mellitus (GDM) remains a significant clinical and public health issue due to its increasing prevalence and the possibility for numerous short- and long-term complications. The growing incidence of GDM seems to coincide with the widespread use of endocrine disrupting chemicals (EDCs). The extensive production and common use of these substances in everyday life has resulted in constant exposure to harmful substances from the environment. That may result in epigenetic changes, which may manifest themselves also after many years and be passed on to future generations. It is important to consider the possible link between environmental exposure to endocrine disrupting chemicals (EDCs) during pregnancy, epigenetic mechanisms and an increased risk for developing gestational diabetes mellitus (GDM). This manuscript attempts to summarize data on epigenetic changes in pregnant women suffering from gestational diabetes in association with EDCs. There is a chance that epigenetic marks may serve as a tool for diagnostic, prognostic, and therapeutic measures. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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35 pages, 3679 KiB  
Review
Dosage Compensation in Females with X-Linked Metabolic Disorders
by Patrycja Juchniewicz, Ewa Piotrowska, Anna Kloska, Magdalena Podlacha, Jagoda Mantej, Grzegorz Węgrzyn, Stefan Tukaj and Joanna Jakóbkiewicz-Banecka
Int. J. Mol. Sci. 2021, 22(9), 4514; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094514 - 26 Apr 2021
Cited by 8 | Viewed by 3522
Abstract
Through the use of new genomic and metabolomic technologies, our comprehension of the molecular and biochemical etiologies of genetic disorders is rapidly expanding, and so are insights into their varying phenotypes. Dosage compensation (lyonization) is an epigenetic mechanism that balances the expression of [...] Read more.
Through the use of new genomic and metabolomic technologies, our comprehension of the molecular and biochemical etiologies of genetic disorders is rapidly expanding, and so are insights into their varying phenotypes. Dosage compensation (lyonization) is an epigenetic mechanism that balances the expression of genes on heteromorphic sex chromosomes. Many studies in the literature have suggested a profound influence of this phenomenon on the manifestation of X-linked disorders in females. In this review, we summarize the clinical and genetic findings in female heterozygotic carriers of a pathogenic variant in one of ten selected X-linked genes whose defects result in metabolic disorders. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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22 pages, 2540 KiB  
Review
DNA Methylation in Solid Tumors: Functions and Methods of Detection
by Andrea Martisova, Jitka Holcakova, Nasim Izadi, Ravery Sebuyoya, Roman Hrstka and Martin Bartosik
Int. J. Mol. Sci. 2021, 22(8), 4247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084247 - 19 Apr 2021
Cited by 45 | Viewed by 8930
Abstract
DNA methylation, i.e., addition of methyl group to 5′-carbon of cytosine residues in CpG dinucleotides, is an important epigenetic modification regulating gene expression, and thus implied in many cellular processes. Deregulation of DNA methylation is strongly associated with onset of various diseases, including [...] Read more.
DNA methylation, i.e., addition of methyl group to 5′-carbon of cytosine residues in CpG dinucleotides, is an important epigenetic modification regulating gene expression, and thus implied in many cellular processes. Deregulation of DNA methylation is strongly associated with onset of various diseases, including cancer. Here, we review how DNA methylation affects carcinogenesis process and give examples of solid tumors where aberrant DNA methylation is often present. We explain principles of methods developed for DNA methylation analysis at both single gene and whole genome level, based on (i) sodium bisulfite conversion, (ii) methylation-sensitive restriction enzymes, and (iii) interactions of 5-methylcytosine (5mC) with methyl-binding proteins or antibodies against 5mC. In addition to standard methods, we describe recent advances in next generation sequencing technologies applied to DNA methylation analysis, as well as in development of biosensors that represent their cheaper and faster alternatives. Most importantly, we highlight not only advantages, but also disadvantages and challenges of each method. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology 2.0)
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