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Epigenomes, Volume 2, Issue 2 (June 2018) – 6 articles

Cover Story (view full-size image): The variability of epigenetic mechanisms offers a wide array of targeting strategies. DNMTs can be targeted with Aza-dC, SGI-110 or Zebularine, affecting CSCs by promoting their differentiation. HDAC inhibitors have also shown promising results, but could have population-specific effects. miRNAs can be complexed within drug-loaded micelles and delivered successfully to cancer cells, and lncRNA can be targeted with GapmeRs or small molecule inhibitors that disrupt lncRNA–protein interactions. View this paper.

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27 pages, 3908 KiB

Open AccessArticle

Salt Stress Induces Non-CG Methylation in Coding Regions of Barley Seedlings (Hordeum vulgare)

by Moumouni Konate, Michael J. Wilkinson, Benjamin T. Mayne, Stephen M. Pederson, Eileen S. Scott, Bettina Berger and Carlos M. Rodriguez Lopez

Epigenomes 2018, 2(2), 12; https://doi.org/10.3390/epigenomes2020012 - 20 Jun 2018

Cited by 22 | Viewed by 9460

Abstract

Salinity can negatively impact crop growth and yield. Changes in DNA methylation are known to occur when plants are challenged by stress and have been associated with the regulation of stress-response genes. However, the role of DNA-methylation in moderating gene expression in response to salt stress has been relatively poorly studied among crops such as barley. Here, we assessed the extent of salt-induced alterations of DNA methylation in barley and their putative role in perturbed gene expression. Using Next Generation Sequencing, we screened the leaf and root methylomes of five divergent barley varieties grown under control and three salt concentrations, to seek genotype independent salt-induced changes in DNA methylation. Salt stress caused increased methylation in leaves but diminished methylation in roots with a higher number of changes in leaves than in roots, indicating that salt induced changes to global methylation are organ specific. Differentially Methylated Markers (DMMs) were mostly located in close proximity to repeat elements, but also in 1094 genes, of which many possessed gene ontology (GO) terms associated with plant responses to stress. Identified markers have potential value as sentinels of salt stress and provide a starting point to allow understanding of the functional role of DNA methylation in facilitating barley’s response to this stressor. Full article

(This article belongs to the Special Issue Plant Epigenome Dynamics)

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13 pages, 704 KiB

Open AccessReview

Recent Advances in Chromatin Mechanisms Controlling Pancreatic Carcinogenesis

by Thomas Hank and Andrew S. Liss

Epigenomes 2018, 2(2), 11; https://doi.org/10.3390/epigenomes2020011 - 20 Jun 2018

Cited by 2 | Viewed by 5272

Abstract

Pancreatic ductal adenocarcinoma has a heterogeneous genetic landscape, marked by frequent mutation of KRAS, CDKN2A, TP53, and SMAD4, resulting in poor responses to conventional therapeutic regimens. Over the past decade, increased understanding of the genetic underpinnings of this lethal cancer has yielded several different characterizations of pancreatic cancer subtypes. However, not all phenotypes and changes in pancreatic cancer can be explained by these findings. New insights on epigenetic modifications associated with pancreatic carcinogenesis have highlighted additional pathways, other than gene mutations, among which chromatin regulation plays a dominant role. Gene expression is highly regulated by subtle changes in chromatin configuration. The underlying mechanism is dominated by reversible post-translational histone modifications. In addition, there is growing evidence that different chromatin mechanisms interact with one another, contributing to the diversity of pancreatic carcinogenesis. This review highlights recent work characterizing chromatin regulatory mechanisms associated with pancreatic carcinogenesis as well as future directions of this emerging research. Full article

(This article belongs to the Special Issue Epigenetics of Pancreatic Cancer)

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28 pages, 1250 KiB

Open AccessReview

The Epigenetic Landscape of Pancreatic Cancer Stem Cells

by Sladjana Zagorac, Laura Garcia-Bermejo and Bruno Sainz, Jr.

Epigenomes 2018, 2(2), 10; https://doi.org/10.3390/epigenomes2020010 - 14 Jun 2018

Cited by 9 | Viewed by 9810

Abstract

Data now indicates that in addition to genetic alterations/mutations, human cancer cells exhibit important changes in their epigenome. In the context of this review, we define the epigenome as the chemical compounds and/or proteins that can interact with nuclear DNA to direct the specific and localized activation or silencing of genes to control the production of cellular proteins (directly or indirectly) in a given cell. Our ever-growing knowledge of how the epigenome can affect cellular processes has largely changed our view of cancer being a solely genetic disease. Nowadays, cancer is largely defined and characterized by the dynamic changes in both the genome and epigenome, which function together and contribute concomitantly to cancer initiation and progression. Since epigenetic modifications are crucial processes involved in controlling cellular identity and lineage fate, perturbations in this layer of gene regulation can contribute to the acquisition of new cellular characteristics different than those that were “initially” intended. For example, aberrant epigenetic alterations may transform normal non-cancer cells into cancer stem cells (CSCs), endowing them with the loss of differentiation and the acquisition of stem-like characteristics. In this review, we will focus our discussion on CSCs in the context of pancreatic ductal adenocarcinoma (PDAC). We will discuss how different epigenetic modifications create a landscape that can impact CSC identity and the way this small sub-population of cells contributes to tumor initiation, progression, and resistance to therapy. Moreover, we will highlight the latest discoveries in epigenetic-based therapies as a means of targeting CSCs. Full article

(This article belongs to the Special Issue Epigenetics of Pancreatic Cancer)

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9 pages, 466 KiB

Open AccessReview

On the Relationships between LncRNAs and Other Orchestrating Regulators: Role of the Circadian System

by Rüdiger Hardeland

Epigenomes 2018, 2(2), 9; https://doi.org/10.3390/epigenomes2020009 - 31 May 2018

Cited by 10 | Viewed by 4268

Abstract

Numerous lncRNAs exhibit circadian rhythms, sometimes with high amplitudes. Therefore, they are controlled by cellular circadian oscillators. However, they also seem to influence circadian clocks, as shown by the important core oscillator gene Per2, at which antiphasic rhythms of Per2 mRNA and its antisense lncRNA are generated. Circadian cycles have also been described for enhancer and super-enhancer lncRNAs. Various lncRNAs are involved in the generation of the rhythm in the pineal gland, which secretes the circadian regulator molecule, melatonin. This compound acts pleiotropically in presumably all tissues and nucleate cells. At least, some of its effects are mediated by sirtuin 1 (SIRT1). SIRT1 enhances circadian amplitudes as an accessory oscillator component and participates in numerous regulation mechanisms. The interrelated actions of circadian oscillators, melatonin and SIRT1 apparently control at least 30% of all coding genes, processes that involve numerous lncRNAs. Full article

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17 pages, 1285 KiB

Open AccessReview

Epigenetic Targeting of Aberrant Transcriptional Modulation in Pancreatic Cancer

by Feda H. Hamdan and Steven A. Johnsen

Epigenomes 2018, 2(2), 8; https://doi.org/10.3390/epigenomes2020008 - 31 May 2018

Cited by 3 | Viewed by 5617

Abstract

While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and Forkhead Box A1 (FOXA1), rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner. Full article

(This article belongs to the Special Issue Epigenetics of Pancreatic Cancer)

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23 pages, 4428 KiB

Open AccessArticle

DNA Methylation Suppression by Bhendi Yellow Vein Mosaic Virus

by Kandhalu Sagadevan Dinesh Babu, Ashirbad Guria, Jeyalakshmi Karanthamalai, Nagesh Srikakulam, Kamlesh Kumari, Priyanka Sharma, Sam Aldrin Chandran, Anburaj Daniel Barnabas, Jebasingh Tennyson and Gopal Pandi

Epigenomes 2018, 2(2), 7; https://doi.org/10.3390/epigenomes2020007 - 31 May 2018

Cited by 8 | Viewed by 7294

Abstract

Bhendi yellow vein mosaic virus (BYVMV) belongs to the monopartite begomovirus associated with the β satellite. As a single-stranded DNA (ssDNA) virus, it should be amenable to transcriptional and post-transcriptional gene silencing (TGS and PTGS). Previously, we had demonstrated C2, C4 and βC1 to be having different levels of influence on PTGS. Hence in the present study, a series of experiments such as agroinfiltration, chop-polymerase chain reaction (PCR), quantitative PCR (qPCR) and bisulfite next generation sequencing (NGS) were designed to analyse the involvement of BYVMV proteins on DNA methylation suppression. From the preliminary studies, we concluded that BYVMV genes were responsible for TGS suppression and C2, C4 genes from BYVMV were selected for further studies. Agroinfiltration experiments with mutant C2 and C4 partial tandem repeat (PTR) constructs of BYVMV have confirmed the role of C2 and C4 in DNA methylation impairment. The protoplast replication assay has shown that C4 was not an impediment for viral DNA replication and subsequent agroinfiltration studies with the C4 mutant BYVMV PTR construct have revealed the involvement of C4 in viral DNA movement. Full article

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