Epigenetics Insights最新文献

{"title":"An Understudied Dimension: Why Age Needs to Be Considered When Studying Epigenetic-Environment Interactions.","authors":"Rio Barrere-Cain,&nbsp;Patrick Allard","doi":"10.1177/2516865720947014","DOIUrl":"https://doi.org/10.1177/2516865720947014","url":null,"abstract":"<p><p>We live in a complex chemical environment where there are an estimated 350 000 chemical compounds or mixtures commercially produced. A strong body of literature shows that there are time points during early development when an organism's epigenome is particularly sensitive to chemicals in its environment. What is less understood is how gene-environment and epigenetic-environment interactions change with age. This question is bidirectional: (1) how do chemicals in the environment affect the aging process and (2) how does aging affect an organism's response to its chemical environment? The study of gene-environment interactions with age is especially important because, in many parts of the world, older individuals are a large and rapidly growing proportion of the population and because aging is a process universal to most of the animal kingdom. Epigenetics has emerged as a crucial framework for studying aging as epigenetic pathways, often triggered by environmental stimuli, have been shown to be essential regulators of the aging process. In this perspective article, we delineate the connection between aging, epigenetics, and environmental exposures. We discuss why it is essential to consider age when researching how an organism interacts with its environment. We describe recent advances in understanding how the chemical environment affects aging and the gap in research on how age affects an organism's response to the environment. Finally, we highlight how model organisms and network approaches can help fill this crucial gap. Taken together, systemic changes that occur in the epigenome with age indicate that adult organisms cannot be treated as a homogeneous population and that there are discrete mechanisms modulating the aging epigenome that we do not yet understand.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":"2516865720947014"},"PeriodicalIF":2.2,"publicationDate":"2020-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720947014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38421576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phthalate Exposures and MicroRNA Expression in Uterine Fibroids: The FORGE Study.","authors":"Ami R Zota,&nbsp;Ruth J Geller,&nbsp;Brianna N VanNoy,&nbsp;Cherie Q Marfori,&nbsp;Sana Tabbara,&nbsp;Lisa Y Hu,&nbsp;Andrea A Baccarelli,&nbsp;Gaby N Moawad","doi":"10.1177/2516865720904057","DOIUrl":"https://doi.org/10.1177/2516865720904057","url":null,"abstract":"<p><p>Phthalates are associated with multiple, adverse reproductive outcomes including increased risk of uterine leiomyoma (fibroids). Phthalates can interact with epigenetic modifications including microRNAs (miRNAs), which help regulate processes crucial to fibroid pathogenesis. However, no prior study has examined the influence of phthalates on miRNA expression in fibroid tumors. We conducted a preliminary, cross-sectional study to examine the associations between phthalate exposures and miRNA expression levels in fibroid tumors and to explore potential effect modification by race/ethnicity. We quantified expression levels of 754 miRNAs in fibroid tumor samples and analyzed spot urine samples for phthalate metabolites collected from 45 pre-menopausal women undergoing surgery for fibroid treatment at an academic hospital. Associations between miRNA levels in fibroids and phthalate biomarkers were evaluated using linear regression adjusting for age, race/ethnicity, and body mass index (BMI). Statistical tests were adjusted for multiple comparisons. We also performed in silico Ingenuity Pathway Analysis to identify the biological pathways that are regulated by phthalate-associated miRNAs. Mono-hydroxybutyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were positively associated with miR-10a-5p (β = 0.76, 95% CI = [0.40, 1.11]) and miR-577 (β = 1.06, 95% CI = [0.53, 1.59]), respectively. A total of 8 phthalate-miRNA associations varied by race/ethnicity (q_interaction < 0.10). Pathway analysis revealed that mRNA gene targets of phthalate-associated miRNAs were significantly associated with multiple fibroid-related processes including angiogenesis, apoptosis, and proliferation of connective tissues. Collectively, these data suggest that exposures to some phthalates are associated with miRNA in fibroids, and that associations may vary by race/ethnicity. Validation of these findings may provide insight into mechanisms underlying associations between phthalates and fibroids and contribute to novel hypotheses regarding racial/ethnic disparities in fibroids.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":"2516865720904057"},"PeriodicalIF":2.2,"publicationDate":"2020-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720904057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37702970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three-Dimensional Genome Organization and Virulence in Apicomplexan Parasites.","authors":"Todd Lenz, Karine G Le Roch","doi":"10.1177/2516865719879436","DOIUrl":"10.1177/2516865719879436","url":null,"abstract":"<p><p>Mounting evidence supports the idea that epigenetic, and the overall 3-dimensional (3D) architecture of the genome, plays an important role in gene expression for eukaryotic organisms. We recently used Hi-C methodologies to generate and compare the 3D genome of 7 different apicomplexan parasites, including several pathogenic and less pathogenic malaria parasites as well as related human parasites <i>Babesia microti</i> and <i>Toxoplasma gondii</i>. Our goal was to understand the possible relationship between genome organization, gene expression, and pathogenicity of these infectious agents. Collectively, our results demonstrate that spatial genome organization in most <i>Plasmodium</i> species is constrained by the colocalization of virulence genes that are unique in their effect on chromosome folding, indicating a link between genome organization and gene expression in more virulent pathogens.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":"2516865719879436"},"PeriodicalIF":3.2,"publicationDate":"2019-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48424292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hiding in Plain Sight: Epigenetic Plasticity in Drug-Induced Tumor Evolution","authors":"Ankur Sharma","doi":"10.1177/2516865719870760","DOIUrl":"https://doi.org/10.1177/2516865719870760","url":null,"abstract":"Cancer is a heterogeneous disease with key differences at the cellular and molecular levels. Acquisition of these differences during the course of tumor development manifests into functional and phenotypic heterogeneity leading to tumor diversity, also referred to as intra-tumor heterogeneity (ITH). Within a tumor, there are subpopulations of cells capable of tumor initiation and maintenance. These cells often exhibit resistance to standard-of-care anti-cancer drugs. However, the role of various subpopulations (clones) in drug resistance remains to be investigated. Moreover, the jury is still out about whether drug resistance is a result of clonal selection of preexisting cells, or the cells acquire resistance by dynamic re-wiring of their epigenome. Therefore, we investigated the drug-induced tumor evolution in patient-derived primary cells of head and neck squamous cell carcinoma. Our data demonstrated the role of a preexisting poised epigenetic state in drug-induced adaptive evolution of tumor cells. Importantly, the combination of chemotherapy and epigenetic inhibitors can prevent/delay drug-induced tumor evolution.","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2019-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719870760","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47604206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence of an Epigenetics System in Archaea","authors":"P. Blum, Sophie Payne","doi":"10.1177/2516865719865280","DOIUrl":"https://doi.org/10.1177/2516865719865280","url":null,"abstract":"Changes in the phenotype of a cell or organism that are heritable but do not involve changes in DNA sequence are referred to as epigenetic. They occur primarily through the gain or loss of chemical modification of chromatin protein or DNA. Epigenetics is therefore a non-Mendelian process. The study of epigenetics in eukaryotes is expanding with advances in knowledge about the relationship between mechanism and phenotype and as a requirement for multicellularity and cancer. However, life also includes other groups or domains, notably the bacteria and archaea. The occurrence of epigenetics in these deep lineages is an emerging topic accompanied by controversy. In these non-eukaryotic organisms, epigenetics is critically important because it stimulates new evolutionary theory and refines perspective about biological action.","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719865280","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48184763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stop-and-Go: Dynamics of Nucleolar Transcription During the Cell Cycle.","authors":"Aishwarya Iyer-Bierhoff,&nbsp;Ingrid Grummt","doi":"10.1177/2516865719849090","DOIUrl":"https://doi.org/10.1177/2516865719849090","url":null,"abstract":"Entry into mitosis correlates with nucleolar disassembly and shutdown of ribosomal RNA (rRNA) gene (rDNA) transcription. In telophase, nucleoli reform and transcription is reactivated. The molecular mechanisms underlying the dynamics of nucleolar transcription during the cell cycle are manifold. Although mitotic inactivation of the RNA polymerase I (Pol I) transcription machinery by posttranslational modifications has been extensively studied, little is known about the structure of rDNA chromatin during progression through mitosis. Methylation of histone H2A at glutamine 104 (H2AQ104me), a dedicated nucleolar histone modification, is lost in prometaphase, leading to chromatin compaction, which enforces mitotic repression of rRNA genes. At telophase, restoration of H2AQ104me is required for the activation of transcription. H2AQ104 methylation and chromatin dynamics are regulated by fibrillarin (FBL) and the NAD+-dependent nucleolar deacetylase sirtuin 7 (SIRT7). Deacetylation of FBL is required for the methylation of H2AQ104 and high levels of rDNA transcription during interphase. At the entry into mitosis, nucleoli disassemble and FBL is hyperacetylated, leading to loss of H2AQ104me, chromatin compaction, and shutdown of Pol I transcription. These results reveal that reversible acetylation of FBL regulates methylation of nucleolar H2AQ104, thereby reinforcing oscillation of Pol I transcription during the cell cycle.","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":"2516865719849090"},"PeriodicalIF":2.2,"publicationDate":"2019-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719849090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37337444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transgenerational Epigenetic Inheritance Is Revealed as a Multi-step Process by Studies of the SET-Domain Proteins SET-25 and SET-32.","authors":"Rachel M Woodhouse,&nbsp;Alyson Ashe","doi":"10.1177/2516865719844214","DOIUrl":"https://doi.org/10.1177/2516865719844214","url":null,"abstract":"<p><p>It is now clear that heredity is not determined purely by Mendelian genetic inheritance; sometimes, epigenetic signals can be passed from parent to progeny for multiple generations. This phenomenon is termed transgenerational epigenetic inheritance (TEI), and examples have now been observed in multiple organisms including plants, flies, mice, and nematodes. Here we discuss the recent findings that TEI is a multi-step process and that the putative chromatin modifiers SET-25 and SET-32 are important in the establishment but not maintenance of silencing.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":"2516865719844214"},"PeriodicalIF":2.2,"publicationDate":"2019-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719844214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37182322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine?","authors":"Gloria Ravegnini,&nbsp;Riccardo Ricci","doi":"10.1177/2516865719842534","DOIUrl":"https://doi.org/10.1177/2516865719842534","url":null,"abstract":"<p><p>Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. <i>KIT/PDGFRA</i>-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O⁶-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of <i>MGMT</i> methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of <i>MGMT</i> methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":"2516865719842534"},"PeriodicalIF":2.2,"publicationDate":"2019-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719842534","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37182321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms.","authors":"Shahad A Qadi,&nbsp;Mohammed A Hassan,&nbsp;Ryan A Sheikh,&nbsp;Othman As Baothman,&nbsp;Mazin A Zamzami,&nbsp;Hani Choudhry,&nbsp;Abdulrahman Labeed Al-Malki,&nbsp;Ashwag Albukhari,&nbsp;Mahmoud Alhosin","doi":"10.1177/2516865719839011","DOIUrl":"https://doi.org/10.1177/2516865719839011","url":null,"abstract":"<p><p>The epigenetic silencing of tumor suppressor genes (TSGs) is a common finding in several solid and hematological tumors involving various epigenetic readers and writers leading to enhanced cell proliferation and defective apoptosis. Thymoquinone (TQ), the major biologically active compound of black seed oil, has demonstrated anticancer activities in various tumors by targeting several pathways. However, its effects on the epigenetic code of cancer cells are largely unknown. In the present study, we performed RNA sequencing to investigate the anticancer mechanisms of TQ-treated T-cell acute lymphoblastic leukemia cell line (Jurkat cells) and examined gene expression using different tools. We found that many key epigenetic players, including ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (<i>UHRF1), DNMT1,3A,3B, G9A, HDAC1,4,9, KDM1B</i>, and <i>KMT2A,B,C,D,E</i>, were downregulated in TQ-treated Jurkat cells. Interestingly, several TSGs, such as <i>DLC1, PPARG, ST7, FOXO6, TET2, CYP1B1, SALL4</i>, and <i>DDIT3</i>, known to be epigenetically silenced in various tumors, including acute leukemia, were upregulated, along with the upregulation of several downstream pro-apoptotic genes, such as <i>RASL11B, RASD1, GNG3, BAD</i>, and <i>BIK</i>. Data obtained from RNA sequencing were confirmed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) in Jurkat cells, as well as in a human breast cancer cell line (MDA-MB-468 cells). We found that the decrease in cell proliferation and in the expression of <i>UHRF1, DNMT1, G9a</i>, and <i>HDAC1</i> genes in both cancer cell (Jurkat cells and MDA-MB-468 cells) lines depends on the TQ dose. Our results indicate that the use of TQ as an epigenetic drug represents a promising strategy for epigenetic therapy for both solid and blood tumors by targeting both DNA methylation and histone post-translational modifications.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":"2516865719839011"},"PeriodicalIF":2.2,"publicationDate":"2019-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719839011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37391148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Classifiers for Precision Diagnosis of Brain Tumors.","authors":"Javier Ij Orozco,&nbsp;Ayla O Manughian-Peter,&nbsp;Matthew P Salomon,&nbsp;Diego M Marzese","doi":"10.1177/2516865719840284","DOIUrl":"https://doi.org/10.1177/2516865719840284","url":null,"abstract":"<p><p>DNA methylation profiling has proven to be a powerful analytical tool, which can accurately identify the tissue of origin of a wide range of benign and malignant neoplasms. Using microarray-based profiling and supervised machine learning algorithms, we and other groups have recently unraveled DNA methylation signatures capable of aiding the histomolecular diagnosis of different tumor types. We have explored the methylomes of metastatic brain tumors from patients with lung cancer, breast cancer, and cutaneous melanoma and primary brain neoplasms to build epigenetic classifiers. Our brain metastasis methylation (BrainMETH) classifier has the ability to determine the type of brain tumor, the origin of the metastases, and the clinical-therapeutic subtype for patients with breast cancer brain metastases. To facilitate the translation of these epigenetic classifiers into clinical practice, we selected and validated the most informative genomic regions utilizing quantitative methylation-specific polymerase chain reaction (qMSP). We believe that the refinement, expansion, integration, and clinical validation of BrainMETH and other recently developed epigenetic classifiers will significantly contribute to the development of more comprehensive and accurate systems for the personalized management of patients with brain metastases.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":" ","pages":"2516865719840284"},"PeriodicalIF":2.2,"publicationDate":"2019-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719840284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37137079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}