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Epigenomes, Volume 2, Issue 3 (September 2018) – 5 articles

Cover Story (view full-size image): Epigenomic dynamics impact pancreatic cancer development, yet other nuclear features may also participate in pancreatic oncogenesis. The LINC complex, the nuclear pore, and the nuclear lamina illustrated here regulate epigenomic processes in normal development. Their dysregulation contributes to the biology of many cancers including pancreatic carcinomas. Thus, understanding these nuclear envelope components is an attractive focus to aid in designing strategies to combat pancreatic neoplasia.View Paper here.

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11 pages, 1030 KiB

Open AccessArticle

The Cytoplasm Affects the Epigenome in Drosophila melanogaster

by Christoph Grunau, Susanne Voigt, Ralph Dobler, Damian K. Dowling and Klaus Reinhardt

Epigenomes 2018, 2(3), 17; https://doi.org/10.3390/epigenomes2030017 - 9 Sep 2018

Cited by 3 | Viewed by 6340

Abstract

Cytoplasmic components and their interactions with the nuclear genome may mediate patterns of phenotypic expression to form a joint inheritance system. However, proximate mechanisms underpinning these interactions remain elusive. To independently assess nuclear genetic and epigenetic cytoplasmic effects, we created a full-factorial design in which representative cytoplasms and nuclear backgrounds from each of two geographically disjunct populations of Drosophila melanogaster were matched together in all four possible combinations. To capture slowly-accumulating epimutations in addition to immediately occurring ones, these constructed populations were examined one year later. We found the K4 methylation of histone H3, H3K4me3, an epigenetic marker associated with transcription start-sites had diverged across different cytoplasms. The loci concerned mainly related to metabolism, mitochondrial function, and reproduction. We found little overlap (<8%) in sites that varied genetically and epigenetically, suggesting that epigenetic changes have diverged independently from any cis-regulatory sequence changes. These results are the first to show cytoplasm-specific effects on patterns of nuclear histone methylation. Our results highlight that experimental nuclear-cytoplasm mismatch may be used to provide a platform to identify epigenetic candidate loci to study the molecular mechanisms of cyto-nuclear interactions. Full article

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17 pages, 1985 KiB

Open AccessReview

Targeting EZH2 in Multiple Myeloma—Multifaceted Anti-Tumor Activity

by Mohammad Alzrigat, Helena Jernberg-Wiklund and Jonathan D. Licht

Epigenomes 2018, 2(3), 16; https://doi.org/10.3390/epigenomes2030016 - 3 Sep 2018

Cited by 18 | Viewed by 6998

Abstract

The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated with repression of gene expression programs related to stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. EZH2 is deregulated and subjected to gain of function or loss of function mutations, and hence functions as an oncogene or tumor suppressor gene in a context-dependent manner. The development of highly selective inhibitors against the histone methyltransferase activity of EZH2 has also contributed to insight into the role of EZH2 and PRC2 in tumorigenesis, and their potential as therapeutic targets in cancer. EZH2 can function as an oncogene in multiple myeloma (MM) by repressing tumor suppressor genes that control apoptosis, cell cycle control and adhesion properties. Taken together these findings have raised the possibility that EZH2 inhibitors could be a useful therapeutic modality in MM alone or in combination with other targeted agents in MM. Therefore, we review the current knowledge on the regulation of EZH2 and its biological impact in MM, the anti-myeloma activity of EZH2 inhibitors and their potential as a targeted therapy in MM. Full article

(This article belongs to the Special Issue Polycomb and Trithorax Group of Proteins in Development and Disease)

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19 pages, 745 KiB

Open AccessReview

Nuclear Envelope Regulation of Oncogenic Processes: Roles in Pancreatic Cancer

by Claudia C. Preston and Randolph S. Faustino

Epigenomes 2018, 2(3), 15; https://doi.org/10.3390/epigenomes2030015 - 2 Sep 2018

Cited by 2 | Viewed by 7602

Abstract

Pancreatic cancer is an aggressive and intractable malignancy with high mortality. This is due in part to a high resistance to chemotherapeutics and radiation treatment conferred by diverse regulatory mechanisms. Among these, constituents of the nuclear envelope play a significant role in regulating oncogenesis and pancreatic tumor biology, and this review focuses on three specific components and their roles in cancer. The LINC complex is a nuclear envelope component formed by proteins with SUN and KASH domains that interact in the periplasmic space of the nuclear envelope. These interactions functionally and structurally couple the cytoskeleton to chromatin and facilitates gene regulation informed by cytoplasmic activity. Furthermore, cancer cell invasiveness is impacted by LINC complex biology. The nuclear lamina is adjacent to the inner nuclear membrane of the nuclear envelope and can actively regulate chromatin in addition to providing structural integrity to the nucleus. A disrupted lamina can impart biophysical compromise to nuclear structure and function, as well as form dysfunctional micronuclei that may lead to genomic instability and chromothripsis. In close relationship to the nuclear lamina is the nuclear pore complex, a large megadalton structure that spans both outer and inner membranes of the nuclear envelope. The nuclear pore complex mediates bidirectional nucleocytoplasmic transport and is comprised of specialized proteins called nucleoporins that are overexpressed in many cancers and are diagnostic markers for oncogenesis. Furthermore, recent demonstration of gene regulatory functions for discrete nucleoporins independent of their nuclear trafficking function suggests that these proteins may contribute more to malignant phenotypes beyond serving as biomarkers. The nuclear envelope is thus a complex, intricate regulator of cell signaling, with roles in pancreatic tumorigenesis and general oncogenic transformation. Full article

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

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19 pages, 3530 KiB

Open AccessArticle

Dynamics of the Methylome and Transcriptome during the Regeneration of Rice

by Fei-Man Hsu, Moloya Gohain, Archana Allishe, Yan-Jiun Huang, Jo-Ling Liao, Lin-Yun Kuang and Pao-Yang Chen

Epigenomes 2018, 2(3), 14; https://doi.org/10.3390/epigenomes2030014 - 21 Jul 2018

Cited by 16 | Viewed by 7357

Abstract

Oryza sativa indica (cv. IR64) and Oryza sativa japonica (cv. TNG67) vary in their regeneration efficiency. Such variation may occur in response to cultural environments that induce somaclonal variation. Somaclonal variations may arise from epigenetic factors, such as DNA methylation. We hypothesized that somaclonal variation may be associated with the differential regeneration efficiency between IR64 and TNG67 through changes in DNA methylation. We generated the stage-associated methylome and transcriptome profiles of the embryo, induced calli, sub-cultured calli, and regenerated calli (including both successful and failed regeneration) of IR64 and TNG67. We found that stage-associated changes are evident by the increase in the cytosine methylation of all contexts upon induction and decline upon regeneration. These changes in the methylome are largely random, but a few regions are consistently targeted at the later stages of culture. The expression profiles showed a dominant tissue-specific difference between the embryo and the calli. A prominent cultivar-associated divide in the global methylation pattern was observed, and a subset of cultivar-associated differentially methylated regions also showed stage-associated changes, implying a close association between differential methylation and the regeneration programs of these two rice cultivars. Based on these findings, we speculate that the differential epigenetic regulation of stress response and developmental pathways may be coupled with genetic differences, ultimately leading to differential regeneration efficiency. The present study elucidates the impact of tissue culture on callus formation and delineates the impact of stage and cultivar to determine the dynamics of the methylome and transcriptome in culture. Full article

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

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11 pages, 985 KiB

Open AccessPerspective

Cancer Risks Linked to the Bad Luck Hypothesis and Epigenomic Mutational Signatures

by José E. Belizário

Epigenomes 2018, 2(3), 13; https://doi.org/10.3390/epigenomes2030013 - 20 Jul 2018

Cited by 3 | Viewed by 4611

Abstract

Exposure to pathogen infection, and occupational and environmental agents, contributes to induction of most types of cancer through different mechanisms. Cancer is defined and characterized by accumulation of mutations and epimutations that lead to changes in the cellular genome and epigenome. According to a recent Bad Luck Hypothesis, random error mutations during DNA replication in a small population of stem cells may be implicated in two-thirds of variation of cancer risk in 25 organs and tissues. What determines stem cell vulnerability and risk of malignancy across the spectrum of organs, such as the brain, bone marrow, skeletal muscles, skin, and liver? Have stem cells pooled in particular tissues or organs evolved some critical ability to deal with DNA damage in the presence of extrinsic environmental factors? This paper describes how the complex replication and repair DNA systems control mutational events. In addition, recent advances on cancer epigenomic signatures and epigenetic mechanisms are discussed, which will guide future investigation of the origin of cancer initiating cells in tissue and organs in a clinical setting. Full article

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