Epigenetics InsightsPub Date : 2020-07-20eCollection Date: 2020-01-01DOI: 10.1177/2516865720938669
Christine A Rygiel, Dana C Dolinoy, Wei Perng, Tamara R Jones, Maritsa Solano, Howard Hu, Martha M Téllez-Rojo, Karen E Peterson, Jaclyn M Goodrich
{"title":"Trimester-Specific Associations of Prenatal Lead Exposure With Infant Cord Blood DNA Methylation at Birth.","authors":"Christine A Rygiel, Dana C Dolinoy, Wei Perng, Tamara R Jones, Maritsa Solano, Howard Hu, Martha M Téllez-Rojo, Karen E Peterson, Jaclyn M Goodrich","doi":"10.1177/2516865720938669","DOIUrl":"10.1177/2516865720938669","url":null,"abstract":"<p><p>Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within <i>PDGFRL</i> associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within <i>TRHR</i> with tibia bone Pb (adjusted <i>P</i>-value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted <i>P</i>-value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2020-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3f/87/10.1177_2516865720938669.PMC7372614.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38221164","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}
Epigenetics InsightsPub Date : 2020-06-16eCollection Date: 2020-01-01DOI: 10.1177/2516865720932146
Valeska Stonawski, Jakob Roetner, Tamme W Goecke, Peter A Fasching, Matthias W Beckmann, Johannes Kornhuber, Oliver Kratz, Gunther H Moll, Anna Eichler, Hartmut Heinrich, Stefan Frey
{"title":"Genome-Wide DNA Methylation Patterns in Children Exposed to Nonpharmacologically Treated Prenatal Depressive Symptoms: Results From 2 Independent Cohorts.","authors":"Valeska Stonawski, Jakob Roetner, Tamme W Goecke, Peter A Fasching, Matthias W Beckmann, Johannes Kornhuber, Oliver Kratz, Gunther H Moll, Anna Eichler, Hartmut Heinrich, Stefan Frey","doi":"10.1177/2516865720932146","DOIUrl":"10.1177/2516865720932146","url":null,"abstract":"<p><strong>Background: </strong>Maternal depressive symptoms are a common phenomenon during pregnancy and are related to negative outcomes for child development and health. Modifications in child DNA methylation are discussed as an underlying mechanism for the association between prenatal depressive symptoms and alterations in child outcomes. However, formerly reported genome-wide associations have yet to be replicated.</p><p><strong>Methods: </strong>In an epigenome-wide association study (EWAS), alterations of DNA methylation related to maternal prenatal depressive symptoms were investigated in buccal cell samples from 174 children (n = 52 exposed to prenatal depressive symptoms; 6-9 years old) of the German longitudinal study FRAMES-FRANCES. Whole blood samples from the independent, age-comparable ARIES subsample of the ARIES/ALSPAC study (n = 641; n = 159 exposed to prenatal depressive symptoms; 7-8 years old) were examined as a confirmation sample. Depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale. DNA methylation was analyzed with the Infinium Human Methylation 450k BeadChip. Modifications in single CpGs, regions, and biological pathways were investigated. Results were adjusted for age and birth outcomes as well as postnatal and current maternal depressive symptoms. Analyses were performed for the whole sample as well as separated for sex.</p><p><strong>Results: </strong>The EWAS yielded no differentially methylated CpG or region as well as no accordance between samples withstanding correction for multiple testing. In pathway analyses, no overlapping functional domain was found to be enriched for either sample. A comparison of current and former findings suggests some overlapping methylation modifications from infancy to childhood. Results suggest that there might be sex-specific differential methylation, which should be further investigated in additional studies.</p><p><strong>Conclusions: </strong>The current, mainly nonsignificant, results challenge the assumption of consistent modifications of DNA methylation in children exposed to prenatal depressive symptoms. Despite the relatively small sample size used in this study, this lack of significant results may reflect diverse issues of environmental epigenetic studies, which need to be addressed in future research.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e5/0c/10.1177_2516865720932146.PMC7298426.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38094623","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}
Epigenetics InsightsPub Date : 2020-04-13eCollection Date: 2020-01-01DOI: 10.1177/2516865720913253
Eline M Bunnik, Marjolein Timmers, Ineke Lle Bolt
{"title":"Ethical Issues in Research and Development of Epigenome-wide Technologies.","authors":"Eline M Bunnik, Marjolein Timmers, Ineke Lle Bolt","doi":"10.1177/2516865720913253","DOIUrl":"https://doi.org/10.1177/2516865720913253","url":null,"abstract":"<p><p>To date, few scholarly discussions on ethical implications of epigenetics and epigenomics technologies have focused on the current phase of research and development, in which researchers are confronted with real and practical ethical dilemmas. In this article, a responsible research and innovation approach, using interviews and an expert meeting, is applied to a case of epigenomic test development for cervical cancer screening. This article provides an overview of ethical issues presently facing epigenomics researchers and test developers, and discusses 3 sets of issues in depth: (1) informed consent; (2) communication with donors and/or research participants, and (3) privacy and publication of data and research results. Although these issues are familiar to research ethics, some aspects are new and most require reinterpretation in the context of epigenomics technologies. With this article, we aim to start a discussion of the practical ethical issues rising in research and development of epigenomic technologies and to offer guidance for researchers working in the field of epigenetic and epigenomic technology.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720913253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37853556","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}
Epigenetics InsightsPub Date : 2020-03-03eCollection Date: 2020-01-01DOI: 10.1177/2516865720910155
Tao Zhu, Anthony P Brown, Hong Ji
{"title":"The Emerging Role of Ten-Eleven Translocation 1 in Epigenetic Responses to Environmental Exposures.","authors":"Tao Zhu, Anthony P Brown, Hong Ji","doi":"10.1177/2516865720910155","DOIUrl":"10.1177/2516865720910155","url":null,"abstract":"<p><p>Mounting evidence from epidemiological studies and animal models has linked exposures to environmental factors to changes in epigenetic markers, especially in DNA methylation. These epigenetic changes may lead to dysregulation of molecular processes and functions and mediate the impact of environmental exposures in complex diseases. However, detailed molecular events that result in epigenetic changes following exposures remain unclear. Here, we review the emerging evidence supporting a critical role of ten-eleven translocation 1 (TET1) in mediating these processes. Targeting TET1 and its associated pathways may have therapeutic potential in alleviating negative impacts of environmental exposures, preventing and treating exposure-related diseases.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2020-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a2/6a/10.1177_2516865720910155.PMC7054729.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37732208","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}
Epigenetics InsightsPub Date : 2020-02-28eCollection Date: 2020-01-01DOI: 10.1177/2516865720904052
Seyed Mohammad Kazem Aghamir, Ramin Heshmat, Mehdi Ebrahimi, Fatemeh Khatami
{"title":"Liquid Biopsy: The Unique Test for Chasing the Genetics of Solid Tumors.","authors":"Seyed Mohammad Kazem Aghamir, Ramin Heshmat, Mehdi Ebrahimi, Fatemeh Khatami","doi":"10.1177/2516865720904052","DOIUrl":"10.1177/2516865720904052","url":null,"abstract":"<p><p>Blood test is a kind of liquid biopsy that checks cancer cells or cancer nucleic acids circulating freely from cells in the blood. A liquid biopsy may be used to distinguish cancer at early stages and it could be a game-changer for both cancer diagnosis and prognosis strategies. Liquid biopsy tests consider several tumor components, such as DNA, RNA, proteins, and the tiny vesicles originating from tumor cells. Actually, liquid biopsy signifies the genetic alterations of tumors through nucleic acids or cells in various body fluids, including blood, urine, cerebrospinal fluid, or saliva in a noninvasive manner. In this review, we present an overall description of liquid biopsy in which circulating tumor cells, cell-free nucleic acids, exosomes, and extrachromosomal circular DNA are included.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37732207","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}
Epigenetics InsightsPub Date : 2020-02-18eCollection Date: 2020-01-01DOI: 10.1177/2516865720904057
Ami R Zota, Ruth J Geller, Brianna N VanNoy, Cherie Q Marfori, Sana Tabbara, Lisa Y Hu, Andrea A Baccarelli, Gaby N Moawad
{"title":"Phthalate Exposures and MicroRNA Expression in Uterine Fibroids: The FORGE Study.","authors":"Ami R Zota, Ruth J Geller, Brianna N VanNoy, Cherie Q Marfori, Sana Tabbara, Lisa Y Hu, Andrea A Baccarelli, 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<sub>interaction</sub> < 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":null,"pages":null},"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}
Jaclyn M Goodrich, Emily C Hector, Lu Tang, Jennifer L LaBarre, Dana C Dolinoy, Adriana Mercado-Garcia, Alejandra Cantoral, Peter Xk Song, Martha Maria Téllez-Rojo, Karen E Peterson
{"title":"Integrative Analysis of Gene-Specific DNA Methylation and Untargeted Metabolomics Data from the ELEMENT Cohort.","authors":"Jaclyn M Goodrich, Emily C Hector, Lu Tang, Jennifer L LaBarre, Dana C Dolinoy, Adriana Mercado-Garcia, Alejandra Cantoral, Peter Xk Song, Martha Maria Téllez-Rojo, Karen E Peterson","doi":"10.1177/2516865720977888","DOIUrl":"https://doi.org/10.1177/2516865720977888","url":null,"abstract":"<p><p>Epigenetic modifications, such as DNA methylation, influence gene expression and cardiometabolic phenotypes that are manifest in developmental periods in later life, including adolescence. Untargeted metabolomics analysis provide a comprehensive snapshot of physiological processes and metabolism and have been related to DNA methylation in adults, offering insights into the regulatory networks that influence cellular processes. We analyzed the cross-sectional correlation of blood leukocyte DNA methylation with 3758 serum metabolite features (574 of which are identifiable) in 238 children (ages 8-14 years) from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study. Associations between these features and percent DNA methylation in adolescent blood leukocytes at LINE-1 repetitive elements and genes that regulate early life growth (<i>IGF2, H19, HSD11B2</i>) were assessed by mixed effects models, adjusting for sex, age, and puberty status. After false discovery rate correction (FDR <i>q</i> < 0.05), 76 metabolites were significantly associated with LINE-1 DNA methylation, 27 with <i>HSD11B2</i>, 103 with <i>H19</i>, and 4 with <i>IGF2</i>. The ten identifiable metabolites included dicarboxylic fatty acids (five associated with LINE-1 or <i>H19</i> methylation at <i>q</i> < 0.05) and 1-octadecanoyl-rac-glycerol (<i>q</i> < 0.0001 for association with <i>H19</i> and <i>q</i> = 0.04 for association with LINE-1). We then assessed the association between these ten known metabolites and adiposity 3 years later. Two metabolites, dicarboxylic fatty acid 17:3 and 5-oxo-7-octenoic acid, were inversely associated with measures of adiposity (<i>P</i> < .05) assessed approximately 3 years later in adolescence. In stratified analyses, sex-specific and puberty-stage specific (Tanner stage = 2 to 5 vs Tanner stage = 1) associations were observed. Most notably, hundreds of statistically significant associations were observed between <i>H19</i> and LINE-1 DNA methylation and metabolites among children who had initiated puberty. Understanding relationships between subclinical molecular biomarkers (DNA methylation and metabolites) may increase our understanding of genes and biological pathways contributing to metabolic changes that underlie the development of adiposity during adolescence.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720977888","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9358739","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":"T. Lenz, K. L. Le Roch","doi":"10.1177/2516865719879436","DOIUrl":"https://doi.org/10.1177/2516865719879436","url":null,"abstract":"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 Babesia microti and Toxoplasma gondii. 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 Plasmodium 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.","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719879436","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48424292","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":"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":null,"pages":null},"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}
Epigenetics InsightsPub Date : 2019-07-18eCollection Date: 2019-01-01DOI: 10.1177/2516865719865282
Erin R Aho, April M Weissmiller, Stephen W Fesik, William P Tansey
{"title":"Targeting WDR5: A WINning Anti-Cancer Strategy?","authors":"Erin R Aho, April M Weissmiller, Stephen W Fesik, William P Tansey","doi":"10.1177/2516865719865282","DOIUrl":"10.1177/2516865719865282","url":null,"abstract":"<p><p>WDR5 is a component of multiple epigenetic regulatory complexes, including the mixed lineage leukemia (MLL)/SET complexes that deposit histone H3 lysine 4 methylation. Inhibitors of an arginine-binding cavity in WDR5, known as the WDR5-interaction (WIN) site, have been proposed to selectively kill MLL-rearranged malignancies via an epigenetic mechanism. We discovered potent WIN site inhibitors and found that they kill MLL cancer cells not through changes in histone methylation, but by displacing WDR5 from chromatin at protein synthesis genes, choking the translational capacity of these cells, and inducing death via a nucleolar stress response. The mechanism of action of WIN site inhibitors reveals new aspects of WDR5 function and forecasts broad therapeutic utility as anti-cancer agents.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2019-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66048977","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}