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https://www.readbyqxmd.com/read/28986391/altered-hydroxymethylation-is-seen-at-regulatory-regions-in-pancreatic-cancer-and-regulates-oncogenic-pathways
#1
Sanchari Bhattacharyya, Kith Pradhan, Nathaniel Campbell, Jozef Mazdo, Aparna Vasantkumar, Shahina Maqbool, Tushar D Bhagat, Sonal Gupta, Masako Suzuki, Yiting Yu, John M Greally, Ulrich Steidl, James Bradner, Meelad Dawlaty, Lucy Godley, Anirban Maitra, Amit Verma
Transcriptional deregulation of oncogenic pathways is a hallmark of cancer and can be due to epigenetic alterations. 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC-enriched loci with hmC-seal was conducted in a cohort of low-passage pancreatic cancer cell lines, primary patient-derived xenografts, and pancreatic controls and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected known regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers...
November 2017: Genome Research
https://www.readbyqxmd.com/read/28958911/applying-omics-technologies-in-chemicals-risk-assessment-report-of-an-ecetoc-workshop
#2
Roland Buesen, Brian N Chorley, Beatriz da Silva Lima, George Daston, Lize Deferme, Timothy Ebbels, Timothy W Gant, Amber Goetz, John Greally, Laura Gribaldo, Jörg Hackermüller, Bruno Hubesch, Danyel Jennen, Kamin Johnson, Jun Kanno, Hans-Martin Kauffmann, Madeleine Laffont, Patrick McMullen, Richard Meehan, Mark Pemberton, Stefania Perdichizzi, Aldert H Piersma, Ursula G Sauer, Kerstin Schmidt, Hervé Seitz, Kayo Sumida, Knut E Tollefsen, Weida Tong, Tewes Tralau, Ben van Ravenzwaay, Ralf J M Weber, Andrew Worth, Carole Yauk, Alan Poole
Prevailing knowledge gaps in linking specific molecular changes to apical outcomes and methodological uncertainties in the generation, storage, processing, and interpretation of 'omics data limit the application of 'omics technologies in regulatory toxicology. Against this background, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop Applying 'omics technologies in chemicals risk assessment that is reported herein. Ahead of the workshop, multi-expert teams drafted frameworks on best practices for (i) a Good-Laboratory Practice-like context for collecting, storing and curating 'omics data; (ii) the processing of 'omics data; and (iii) weight-of-evidence approaches for integrating 'omics data...
September 25, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28911167/in-utero-exposure-to-a-high-fat-diet-programs-hepatic-hypermethylation-and-gene-dysregulation-and-development-of-metabolic-syndrome-in-male-mice
#3
Yoshinori Seki, Masako Suzuki, Xingyi Guo, Alan Scott Glenn, Patricia M Vuguin, Ariana Fiallo, Quan Du, Yi-An Ko, Yiting Yu, Katalin Susztak, Deyou Zheng, John M Greally, Ellen B Katz, Maureen J Charron
Exposure to a high-fat (HF) diet in utero is associated with increased incidence of cardiovascular disease, diabetes, and metabolic syndrome later in life. However, the molecular basis of this enhanced susceptibility for metabolic disease is poorly understood. Gene expression microarray and genome-wide DNA methylation analyses of mouse liver revealed that exposure to a maternal HF milieu activated genes of immune response, inflammation, and hepatic dysfunction. DNA methylation analysis revealed 3360 differentially methylated loci, most of which (76%) were hypermethylated and distributed preferentially to hotspots on chromosomes 4 [atherosclerosis susceptibility quantitative trait loci (QTLs) 1] and 18 (insulin-dependent susceptibility QTLs 21)...
September 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28684528/epigenetically-aberrant-stroma-in-mds-propagates-disease-via-wnt-%C3%AE-catenin-activation
#4
Tushar D Bhagat, Si Chen, Matthias Bartenstein, A Trevor Barlowe, Dagny Von Ahrens, Gaurav S Choudhary, Patrick Tivnan, Elianna Amin, A Mario Marcondes, Mathijs A Sanders, Remco M Hoogenboezem, Suman Kambhampati, Nandini Ramachandra, Iaonnis Mantzaris, Vineeth Sukrithan, Remi Laurence, Robert Lopez, Prafullla Bhagat, Orsi Giricz, Davendra Sohal, Amittha Wickrema, Cecilia Yeung, Kira Gritsman, Peter Aplan, Konrad Hochedlinger, Yiting Yu, Kith Pradhan, Jinghang Zhang, John M Greally, Siddhartha Mukherjee, Andrea Pellagatti, Jacqueline Boultwood, Britta Will, Ulrich Steidl, Marc H G P Raaijmakers, H Joachim Deeg, Michael G Kharas, Amit Verma
The bone marrow microenvironment influences malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. In addition, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we conducted a DNA methylome analysis of bone marrow-derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28629478/genetic-epigenetic-interactions-in-cis-a-major-focus-in-the-post-gwas-era
#5
REVIEW
Catherine Do, Alyssa Shearer, Masako Suzuki, Mary Beth Terry, Joel Gelernter, John M Greally, Benjamin Tycko
Studies on genetic-epigenetic interactions, including the mapping of methylation quantitative trait loci (mQTLs) and haplotype-dependent allele-specific DNA methylation (hap-ASM), have become a major focus in the post-genome-wide-association-study (GWAS) era. Such maps can nominate regulatory sequence variants that underlie GWAS signals for common diseases, ranging from neuropsychiatric disorders to cancers. Conversely, mQTLs need to be filtered out when searching for non-genetic effects in epigenome-wide association studies (EWAS)...
June 19, 2017: Genome Biology
https://www.readbyqxmd.com/read/28557546/inflammation-associated-dna-methylation-patterns-in-epithelium-of-ulcerative-colitis
#6
Alan Barnicle, Cathal Seoighe, John M Greally, Aaron Golden, Laurence J Egan
Aberrant DNA methylation patterns have been reported in inflamed tissues and may play a role in disease. We studied DNA methylation and gene expression profiles of purified intestinal epithelial cells from ulcerative colitis patients, comparing inflamed and non-inflamed areas of the colon. We identified 577 differentially methylated sites (false discovery rate <0.2) mapping to 210 genes. From gene expression data from the same epithelial cells, we identified 62 differentially expressed genes with increased expression in the presence of inflammation at prostate cancer susceptibility genes PRAC1 and PRAC2...
May 30, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28555657/associating-cellular-epigenetic-models-with-human-phenotypes
#7
REVIEW
Tuuli Lappalainen, John M Greally
Epigenetic association studies have been carried out to test the hypothesis that environmental perturbations trigger cellular reprogramming, with downstream effects on cellular function and phenotypes. There have now been numerous studies of the potential molecular mediators of epigenetic changes by epigenome-wide association studies (EWAS). However, a challenge for the field is the interpretation of the results obtained. We describe a second-generation EWAS approach, which focuses on the possible cellular models of epigenetic perturbations, studied by rigorous analysis and interpretation of genomic data...
July 2017: Nature Reviews. Genetics
https://www.readbyqxmd.com/read/28479334/cdc42-related-genes-are-upregulated-in-helper-t%C3%A2-cells-from-obese-asthmatic-children
#8
Deepa Rastogi, John Nico, Andrew D Johnston, Toni Adrianne M Tobias, Yurydia Jorge, Fernando Macian, John M Greally
BACKGROUND: Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmatic children have nonatopic TH1-polarized systemic inflammation that correlates with pulmonary function deficits, but the pathways underlying TH1-polarized inflammation are not well understood. OBJECTIVE: We compared the CD4(+) T-cell transcriptome in obese children with asthma with that in normal-weight children with asthma to identify key differentially expressed genes associated with TH1-polarized inflammation...
May 4, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28367533/population-epigenetics
#9
John M Greally
The field of epigenetics is maturing, with increased interest in understanding the normal regulation of the genome and the possibility that it becomes reprogrammed aberrantly as part of the cause of disease phenotypes. Applying the current technologies and insights to the study of human populations is potentially a way of understanding mechanisms and consequences of these diseases. When extended to encompass health care disparities, understanding why certain populations are unusually prone to specific conditions, there is certainly some potential for gaining new and valuable insights, but these studies are likely to be unusually prone to the effects of confounding influences and need to be designed, executed and interpreted with extra care...
February 2017: Current opinion in systems biology
https://www.readbyqxmd.com/read/28100166/smite-an-r-bioconductor-package-that-identifies-network-modules-by-integrating-genomic-and-epigenomic-information
#10
N Ari Wijetunga, Andrew D Johnston, Ryo Maekawa, Fabien Delahaye, Netha Ulahannan, Kami Kim, John M Greally
BACKGROUND: The molecular assays that test gene expression, transcriptional, and epigenetic regulation are increasingly diverse and numerous. The information generated by each type of assay individually gives an insight into the state of the cells tested. What should be possible is to add the information derived from separate, complementary assays to gain higher-confidence insights into cellular states. At present, the analysis of multi-dimensional, massive genome-wide data requires an initial pruning step to create manageable subsets of observations that are then used for integration, which decreases the sizes of the intersecting data sets and the potential for biological insights...
January 18, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/27956497/non-cpg-methylation-by-dnmt3b-facilitates-rest-binding-and-gene-silencing-in-developing-mouse-hearts
#11
Donghong Zhang, Bingruo Wu, Ping Wang, Yidong Wang, Pengfei Lu, Tamilla Nechiporuk, Thomas Floss, John M Greally, Deyou Zheng, Bin Zhou
The dynamic interaction of DNA methylation and transcription factor binding in regulating spatiotemporal gene expression is essential for embryogenesis, but the underlying mechanisms remain understudied. In this study, using mouse models and integration of in vitro and in vivo genetic and epigenetic analyses, we show that the binding of REST (repressor element 1 (RE1) silencing transcription factor; also known as NRSF) to its cognate RE1 sequences is temporally regulated by non-CpG methylation. This process is dependent on DNA methyltransferase 3B (DNMT3B) and leads to suppression of adult cardiac genes in developing hearts...
April 7, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27918756/the-current-state-of-epigenetic-research-in-humans-promise-and-reality
#12
John M Greally, Amanda J Drake
No abstract text is available yet for this article.
February 1, 2017: JAMA Pediatrics
https://www.readbyqxmd.com/read/27909050/notch-pathway-is-activated-via-genetic-and-epigenetic-alterations-and-is-a-therapeutic-target-in-clear-cell-renal-cancer
#13
Tushar D Bhagat, Yiyu Zou, Shizheng Huang, Jihwan Park, Matthew B Palmer, Caroline Hu, Weijuan Li, Niraj Shenoy, Orsolya Giricz, Gaurav Choudhary, Yiting Yu, Yi-An Ko, María C Izquierdo, Ae Seo Deok Park, Nishanth Vallumsetla, Remi Laurence, Robert Lopez, Masako Suzuki, James Pullman, Justin Kaner, Benjamin Gartrell, A Ari Hakimi, John M Greally, Bharvin Patel, Karim Benhadji, Kith Pradhan, Amit Verma, Katalin Susztak
Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival...
January 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27808166/lpa-receptor-activity-is-basal-specific-and-coincident-with-early-pregnancy-and-involution-during-mammary-gland-postnatal-development
#14
Deanna Acosta, Susmita Bagchi, Pilib Ó Broin, Daniel Hollern, Silvia E Racedo, Bernice Morrow, Rani S Sellers, John M Greally, Aaron Golden, Eran Andrechek, Teresa Wood, Cristina Montagna
During pregnancy, luminal and basal epithelial cells of the adult mammary gland proliferate and differentiate resulting in remodeling of the adult gland. While pathways that control this process have been characterized in the gland as a whole, the contribution of specific cell subtypes, in particular the basal compartment, remains largely unknown. Basal cells provide structural and contractile support, however they also orchestrate the communication between the stroma and the luminal compartment at all developmental stages...
November 3, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27557505/a-polycomb-mediated-epigenetic-field-defect-precedes-invasive-cervical-carcinoma
#15
Neil Ari Wijetunga, Miriam Ben-Dayan, Jessica Tozour, Robert D Burk, Nicolas F Schlecht, Mark H Einstein, John M Greally
Human papillomavirus (HPV)-associated cervical carcinoma is preceded by stages of cervical intra-epithelial neoplasia (CIN) that can variably progress to malignancy. Understanding the different molecular processes involved in the progression of pre-malignant CIN is critical to the development of improved predictive and interventional capabilities. We tested the role of regulators of transcription in both the development and the progression of HPV-associated CIN, performing the most comprehensive genomic survey to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27471971/line-1-activity-in-facultative-heterochromatin-formation-during-x-chromosome-inactivation
#16
EDITORIAL
Jennifer C Chow, Constance Ciaudo, Melissa J Fazzari, Nathan Mise, Nicolas Servant, Jacob L Glass, Matthew Attreed, Philip Avner, Anton Wutz, Emmanuel Barillot, John M Greally, Olivier Voinnet, Edith Heard
No abstract text is available yet for this article.
July 28, 2016: Cell
https://www.readbyqxmd.com/read/27458904/epigenetics-cellular-memory-and-gene-regulation
#17
Steven Henikoff, John M Greally
The field described as 'epigenetics' has captured the imagination of scientists and the lay public. Advances in our understanding of chromatin and gene regulatory mechanisms have had impact on drug development, fueling excitement in the lay public about the prospects of applying this knowledge to address health issues. However, when describing these scientific advances as 'epigenetic', we encounter the problem that this term means different things to different people, starting within the scientific community and amplified in the popular press...
July 25, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/27420643/mecp2-binding-cooperativity-inhibits-dna-modification-specific-recognition
#18
Sergei Khrapunov, Yisong Tao, Huiyong Cheng, Camille Padlan, Richard Harris, Aristea S Galanopoulou, John M Greally, Mark E Girvin, Michael Brenowitz
Methyl-CpG binding protein 2 (MeCP2) is a multifunctional protein that guides neuronal development through its binding to DNA, recognition of sites of methyl-CpG (mCpG) DNA modification, and interaction with other regulatory proteins. Our study explores the relationship between mCpG and hydroxymethyl-CpG (hmCpG) recognition mediated by its mCpG binding domain (MBD) and binding cooperativity mediated by its C-terminal polypeptide. Previous study of the isolated MBD of MeCP2 documented an unusual mechanism by which ion uptake is required for discrimination of mCpG and hmCpG from CpG...
August 9, 2016: Biochemistry
https://www.readbyqxmd.com/read/27401842/novel-epigenetic-changes-in-cdkn2a-are-associated-with-progression-of-cervical-intraepithelial-neoplasia
#19
N Ari Wijetunga, Thomas J Belbin, Robert D Burk, Kathleen Whitney, Maria Abadi, John M Greally, Mark H Einstein, Nicolas F Schlecht
OBJECTIVE: To conduct a comprehensive mapping of the genomic DNA methylation in CDKN2A, which codes for the p16(INK4A) and p14(ARF) proteins, and 14 of the most promising DNA methylation marker candidates previously reported to be associated with progression of low-grade cervical intraepithelial neoplasia (CIN1) to cervical cancer. METHODS: We analyzed DNA methylation in 68 HIV-seropositive and negative women with incident CIN1, CIN2, CIN3 and invasive cervical cancer, assaying 120 CpG dinucleotide sites spanning APC, CDH1, CDH13, CDKN2A, CDKN2B, DAPK1, FHIT, GSTP1, HIC1, MGMT, MLH1, RARB, RASSF1, TERT and TIMP3 using the Illumina Infinium array...
September 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/27339364/de-novo-intrachromosomal-gene-conversion-from-opn1mw-to-opn1lw-in-the-male-germline-results-in-blue-cone-monochromacy
#20
Elena Buena-Atienza, Klaus Rüther, Britta Baumann, Richard Bergholz, David Birch, Elfride De Baere, Helene Dollfus, Marie T Greally, Peter Gustavsson, Christian P Hamel, John R Heckenlively, Bart P Leroy, Astrid S Plomp, Jan Willem R Pott, Katherine Rose, Thomas Rosenberg, Zornitza Stark, Joke B G M Verheij, Richard Weleber, Ditta Zobor, Nicole Weisschuh, Susanne Kohl, Bernd Wissinger
X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay...
2016: Scientific Reports
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