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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 August 2020) | Viewed by 55266

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Prof. Dr. Carlo Gaetano

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IRCCS Scientific Clinical Institutes Maugeri (ICS Maugeri), Pavia, Italy
Interests: epigenetics; cardiovascular disease; gene expression; DNA methylation; histone modification
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epigenetics, exploring the interface between environmental signals and the remodeling of chromatin structure, promises to shed light on disease pathogenesis, possibly contributing to the identification of novel therapeutic targets. In this Special Issue, we shall focus on the role of histone code and nonhistone proteins modification, epigenetic enzymes, and DNA methylation, whose function has been frequently associated, often with a controversial role, to the pathogenesis of chronic noncommunicable diseases. Although numerous studies demonstrate that epigenetic pathways are modulated in such pathophysiological conditions, this matter is still under heavy debate. This Special Issue is intended to contribute to the field with original research articles or reviews putting in the spotlight the relevance of epigenetics in chronic diseases, possibly providing indication about future innovative therapeutic approaches. Reports about cancer, cardiovascular, metabolic, muscular, neurodegenerative, bones, and respiratory diseases are welcomed.

Prof. Carlo Gaetanoà
Guest Editor

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Published Papers (10 papers)

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Research

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19 pages, 3485 KiB

Open AccessArticle

Epigenetic Silencing of LMX1A Contributes to Cancer Progression in Lung Cancer Cells

by Ti-Hui Wu, Shan-Yueh Chang, Yu-Lueng Shih, Chih-Feng Chian, Hung Chang and Ya-Wen Lin

Int. J. Mol. Sci. 2020, 21(15), 5425; https://doi.org/10.3390/ijms21155425 - 30 Jul 2020

Cited by 7 | Viewed by 3173

Abstract

Epigenetic modification is considered a major mechanism of the inactivation of tumor suppressor genes that finally contributes to carcinogenesis. LIM homeobox transcription factor 1α (LMX1A) is one of the LIM-homeobox-containing genes that is a critical regulator of growth and differentiation. Recently, LMX1A was shown to be hypermethylated and functioned as a tumor suppressor in cervical cancer, ovarian cancer, and gastric cancer. However, its role in lung cancer has not yet been clarified. In this study, we used public databases, methylation-specific PCR (MSP), reverse transcription PCR (RT-PCR), and bisulfite genomic sequencing to show that LMX1A was downregulated or silenced due to promoter hypermethylation in lung cancers. Treatment of lung cancer cells with the demethylating agent 5-aza-2’-deoxycytidine restored LMX1A expression. In the lung cancer cell lines H23 and H1299, overexpression of LMX1A did not affect cell proliferation but suppressed colony formation and invasion. These suppressive effects were reversed after inhibition of LMX1A expression in an inducible expression system in H23 cells. The quantitative RT-PCR (qRT-PCR) data showed that LMX1A could modulate epithelial mesenchymal transition (EMT) through E-cadherin (CDH1) and fibronectin (FN1). NanoString gene expression analysis revealed that all aberrantly expressed genes were associated with processes related to cancer progression, including angiogenesis, extracellular matrix (ECM) remodeling, EMT, cancer metastasis, and hypoxia-related gene expression. Taken together, these data demonstrated that LMX1A is inactivated through promoter hypermethylation and functions as a tumor suppressor. Furthermore, LMX1A inhibits non-small cell lung cancer (NSCLC) cell invasion partly through modulation of EMT, angiogenesis, and ECM remodeling. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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9 pages, 216 KiB

Open AccessArticle

Interaction of Osteoarthritis and BMI on Leptin Promoter Methylation in Taiwanese Adults

by Tzi-Peng Yang, Hsiao-Mei Chen, Chao-Chin Hu, Li-Yuan Chen, Fen-Fen Shih, Disline Manli Tantoh, Kuan-Jung Lee, Yi-Chia Liaw, Rong-Tzong Tsai and Yung-Po Liaw

Int. J. Mol. Sci. 2020, 21(1), 123; https://doi.org/10.3390/ijms21010123 - 23 Dec 2019

Cited by 7 | Viewed by 3041

Abstract

Leptin (LEP) regulates glucose metabolism and energy storage in the body. Osteoarthritis (OA) is associated with the upregulation of serum LEP. LEP promoter methylation is associated with obesity. So far, few studies have explored the association of BMI and OA with LEP methylation. We assessed the interaction between body mass index (BMI) and OA on LEP promoter methylation. Data of 1114 participants comprising 583 men and 558 women, aged 30–70 years were retrieved from the Taiwan Biobank Database (2008–2015). Osteoarthritis was self-reported and cases were those who reported having ever been clinically diagnosed with osteoarthritis. BMI was categorized into underweight, normal weight, overweight, and obesity. The mean LEP promoter methylation level in individuals with osteoarthritis was 0.5509 ± 0.00437 and 0.5375 ± 0.00101 in those without osteoarthritis. The interaction between osteoarthritis and BMI on LEP promoter methylation was significant (p-value = 0.0180). With normal BMI as the reference, the mean LEP promoter methylation level was significantly higher in obese osteoarthritic individuals (β = 0.03696, p-value = 0.0187). However, there was no significant association between BMI and LEP promoter methylation in individuals without osteoarthritis, regardless of BMI. In conclusion, only obesity was significantly associated with LEP promoter methylation (higher levels) specifically in osteoarthritic patients. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

14 pages, 1765 KiB

Open AccessArticle

A Novel Prognostic DNA Methylation Panel for Colorectal Cancer

by Hsin-Hua Chung, Chih-Chi Kuo, Cheng-Wen Hsiao, Chao-Yang Chen, Je-Ming Hu, Chih-Hsiung Hsu, Yu-Ching Chou, Ya-Wen Lin and Yu-Lueng Shih

Int. J. Mol. Sci. 2019, 20(19), 4672; https://doi.org/10.3390/ijms20194672 - 20 Sep 2019

Cited by 16 | Viewed by 3920

Abstract

Colorectal cancer (CRC) is one of the most common cancers and the second leading cause of cancer-related deaths. Discrepancies in clinical outcomes are observed even among patients with same-stage CRC due to molecular heterogeneity. Thus, biomarkers for predicting prognosis in CRC patients are urgently needed. We previously demonstrated that stage II CRC patients with NKX6.1 methylation had poor 5-year overall survival. However, the methylation frequency of NKX6.1 was only 23% in 151 pairs of CRC tissues. Thus, we aimed to develop a more robust prognostic panel for CRC using NKX6.1 in combination with three genes: LIM homeobox transcription factor 1α (LMX1A), sex-determining region Y-box 1 (SOX1), and zinc finger protein 177 (ZNF177). Through quantitative methylation analysis, we found that LMX1A, SOX1, and ZNF177 were hypermethylated in CRC tissues. LMX1A methylation was significantly associated with poor 5-year overall, and disease-free survivals in stage I and II CRC patients. Sensitivity and specificity analyses of the four-gene combination revealed the best sensitivity and optimal specificity. Moreover, patients with the four-gene methylation profile exhibited poorer disease-free survival than those without methylation. A significant effect of the four-gene methylation status on overall survival and disease-free survival was observed in early stage I and II CRC patients (p = 0.0016 and p = 0.0230, respectively). Taken together, these results demonstrate that the combination of the methylation statuses of NKX6.1, LMX1A, SOX1, and ZNF177 creates a novel prognostic panel that could be considered a molecular marker for outcomes in CRC patients. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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Review

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26 pages, 1069 KiB

Open AccessReview

Epigenetic Regulation of Pulmonary Arterial Hypertension-Induced Vascular and Right Ventricular Remodeling: New Opportunities?

by Jordy M. M. Kocken and Paula A. da Costa Martins

Int. J. Mol. Sci. 2020, 21(23), 8901; https://doi.org/10.3390/ijms21238901 - 24 Nov 2020

Cited by 20 | Viewed by 4872

Abstract

Pulmonary artery hypertension (PAH) is a rare chronic disease with high impact on patients’ quality of life and currently no available cure. PAH is characterized by constant remodeling of the pulmonary artery by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), fibroblasts (FBs) and endothelial cells (ECs). This remodeling eventually leads to increased pressure in the right ventricle (RV) and subsequent right ventricle hypertrophy (RVH) which, when left untreated, progresses into right ventricle failure (RVF). PAH can not only originate from heritable mutations, but also develop as a consequence of congenital heart disease, exposure to drugs or toxins, HIV, connective tissue disease or be idiopathic. While much attention was drawn into investigating and developing therapies related to the most well understood signaling pathways in PAH, in the last decade, a shift towards understanding the epigenetic mechanisms driving the disease occurred. In this review, we reflect on the different epigenetic regulatory factors that are associated with the pathology of RV remodeling, and on their relevance towards a better understanding of the disease and subsequently, the development of new and more efficient therapeutic strategies. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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21 pages, 4238 KiB

Open AccessReview

The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma

by Pradeep Kumar Rajan, Utibe-Abasi Udoh, Juan D. Sanabria, Moumita Banerjee, Gary Smith, Mathew Steven Schade, Jacqueline Sanabria, Komal Sodhi, Sandrine Pierre, Zijian Xie, Joseph I. Shapiro and Juan Sanabria

Int. J. Mol. Sci. 2020, 21(23), 8894; https://doi.org/10.3390/ijms21238894 - 24 Nov 2020

Cited by 40 | Viewed by 9556

Abstract

Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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21 pages, 744 KiB

Open AccessReview

Treating Senescence like Cancer: Novel Perspectives in Senotherapy of Chronic Diseases

by Alessia Mongelli, Sandra Atlante, Veronica Barbi, Tiziana Bachetti, Fabio Martelli, Antonella Farsetti and Carlo Gaetano

Int. J. Mol. Sci. 2020, 21(21), 7984; https://doi.org/10.3390/ijms21217984 - 27 Oct 2020

Cited by 8 | Viewed by 5788

Abstract

The WHO estimated around 41 million deaths worldwide each year for age-related non-communicable chronic diseases. Hence, developing strategies to control the accumulation of cell senescence in living organisms and the overall aging process is an urgently needed problem of social relevance. During aging, many biological processes are altered, which globally induce the dysfunction of the whole organism. Cell senescence is one of the causes of this modification. Nowadays, several drugs approved for anticancer therapy have been repurposed to treat senescence, and others are under scrutiny in vitro and in vivo to establish their senomorphic or senolytic properties. In some cases, this research led to a significant increase in cell survival or to a prolonged lifespan in animal models, at least. Senomorphics can act to interfere with a specific pathway in order to restore the appropriate cellular function, preserve viability, and to prolong the lifespan. On the other hand, senolytics induce apoptosis in senescent cells allowing the remaining non–senescent population to preserve or restore tissue function. A large number of research articles and reviews recently addressed this topic. Herein, we would like to focus attention on those chemical agents with senomorphic or senolytic properties that perspectively, according to literature, suggest a potential application as senotherapeutics for chronic diseases. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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15 pages, 1877 KiB

Open AccessReview

DNA Methylation Profiling for Diagnosing Undifferentiated Sarcoma with Capicua Transcriptional Receptor (CIC) Alterations

by Evelina Miele, Rita De Vito, Andrea Ciolfi, Lucia Pedace, Ida Russo, Maria Debora De Pasquale, Angela Di Giannatale, Alessandro Crocoli, Biagio De Angelis, Marco Tartaglia, Rita Alaggio and Giuseppe Maria Milano

Int. J. Mol. Sci. 2020, 21(5), 1818; https://doi.org/10.3390/ijms21051818 - 6 Mar 2020

Cited by 21 | Viewed by 4008

Abstract

Undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors in the pediatric population. Molecular techniques are instrumental for the categorization and differential diagnosis of these tumors. A subgroup of recently identified soft tissue sarcomas with undifferentiated round cell morphology was characterized by Capicua transcriptional receptor (CIC) rearrangements. Recently, an array-based DNA methylation analysis of undifferentiated tumors with small blue round cell histology was shown to provide a highly robust and reproducible approach for precisely classifying this diagnostically challenging group of tumors. We describe the case of an undifferentiated sarcoma of the abdominal wall in a 12-year-old girl. The patient presented with a voluminous mass of the abdominal wall, and multiple micro-nodules in the right lung. The tumor was unclassifiable with current immunohistochemical and molecular approaches. However, DNA methylation profiling allowed us to classify this neoplasia as small blue round cell tumor with CIC alterations. The patient was treated with neoadjuvant chemotherapy followed by complete surgical resection and adjuvant chemotherapy. After 22 months, the patient is disease-free and in good clinical condition. To put our experience in context, we conducted a literature review, analyzing current knowledge and state-of-the-art diagnosis, prognosis, and clinical management of CIC rearranged sarcomas. Our findings further support the use of DNA methylation profiling as an important tool to improve diagnosis of non-Ewing small round cell tumors. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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28 pages, 465 KiB

Open AccessReview

Early Programming of Adult Systemic Essential Hypertension

by Verónica Guarner-Lans, Abril Ramírez-Higuera, María Esther Rubio-Ruiz, Vicente Castrejón-Téllez, María Elena Soto and Israel Pérez-Torres

Int. J. Mol. Sci. 2020, 21(4), 1203; https://doi.org/10.3390/ijms21041203 - 11 Feb 2020

Cited by 43 | Viewed by 5973

Abstract

Cardiovascular diseases are being included in the study of developmental origins of health and disease (DOHaD) and essential systemic hypertension has also been added to this field. Epigenetic modifications are one of the main mechanisms leading to early programming of disease. Different environmental factors occurring during critical windows in the early stages of life may leave epigenetic cues, which may be involved in the programming of hypertension when individuals reach adulthood. Such environmental factors include pre-term birth, low weight at birth, altered programming of different organs such as the blood vessels and the kidney, and living in disadvantageous conditions in the programming of hypertension. Mechanisms behind these factors that impact on the programming include undernutrition, oxidative stress, inflammation, emotional stress, and changes in the microbiota. These factors and their underlying causes acting at the vascular level will be discussed in this paper. We also explore the establishment of epigenetic cues that may lead to hypertension at the vascular level such as DNA methylation, histone modifications (methylation and acetylation), and the role of microRNAs in the endothelial cells and blood vessel smooth muscle which participate in hypertension. Since epigenetic changes are reversible, the knowledge of this type of markers could be useful in the field of prevention, diagnosis or epigenetic drugs as a therapeutic approach to hypertension. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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22 pages, 1675 KiB

Open AccessReview

Interplay between BRCA1 and GADD45A and Its Potential for Nucleotide Excision Repair in Breast Cancer Pathogenesis

by Sylwia Pietrasik, Gabriela Zajac, Jan Morawiec, Miroslaw Soszynski, Michal Fila and Janusz Blasiak

Int. J. Mol. Sci. 2020, 21(3), 870; https://doi.org/10.3390/ijms21030870 - 29 Jan 2020

Cited by 32 | Viewed by 6245

Abstract

A fraction of breast cancer cases are associated with mutations in the BRCA1 (BRCA1 DNA repair associated, breast cancer type 1 susceptibility protein) gene, whose mutated product may disrupt the repair of DNA double-strand breaks as BRCA1 is directly involved in the homologous recombination repair of such DNA damage. However, BRCA1 can stimulate nucleotide excision repair (NER), the most versatile system of DNA repair processing a broad spectrum of substrates and playing an important role in the maintenance of genome stability. NER removes carcinogenic adducts of diol-epoxy derivatives of benzo[α]pyrene that may play a role in breast cancer pathogenesis as their accumulation is observed in breast cancer patients. NER deficiency was postulated to be intrinsic in stage I of sporadic breast cancer. BRCA1 also interacts with GADD45A (growth arrest and DNA damage-inducible protein GADD45 alpha) that may target NER machinery to actively demethylate genome sites in order to change the expression of genes that may be important in breast cancer. Therefore, the interaction between BRCA1 and GADD45 may play a role in breast cancer pathogenesis through the stimulation of NER, increasing the genomic stability, removing carcinogenic adducts, and the local active demethylation of genes important for cancer transformation. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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24 pages, 1052 KiB

Open AccessReview

The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review

by Lauren M. Webb, Kathryn E. Phillips, Man Choi Ho, Marin Veldic and Caren J. Blacker

Int. J. Mol. Sci. 2020, 21(3), 826; https://doi.org/10.3390/ijms21030826 - 28 Jan 2020

Cited by 49 | Viewed by 7991

Abstract

Major depressive disorder (MDD) is the leading cause of disability worldwide and is associated with high rates of suicide and medical comorbidities. Current antidepressant medications are suboptimal, as most MDD patients fail to achieve complete remission from symptoms. At present, clinicians are unable to predict which antidepressant is most effective for a particular patient, exposing patients to multiple medication trials and side effects. Since MDD’s etiology includes interactions between genes and environment, the epigenome is of interest for predictive utility and treatment monitoring. Epigenetic mechanisms of antidepressant medications are incompletely understood. Differences in epigenetic profiles may impact treatment response. A systematic literature search yielded 24 studies reporting the interaction between antidepressants and eight genes (BDNF, MAOA, SLC6A2, SLC6A4, HTR1A, HTR1B, IL6, IL11) and whole genome methylation. Methylation of certain sites within BDNF, SLC6A4, HTR1A, HTR1B, IL11, and the whole genome was predictive of antidepressant response. Comparing DNA methylation in patients during depressive episodes, during treatment, in remission, and after antidepressant cessation would help clarify the influence of antidepressant medications on DNA methylation. Individuals’ unique methylation profiles may be used clinically for personalization of antidepressant choice in the future. Full article

(This article belongs to the Special Issue Epigenetics of Non-transmissible Diseases)

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