Please note this is a provisional agenda.
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Day 1
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8:00
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Registration
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8:55
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Welcome and Introduction
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9:00
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Epigenomics of Differential Diagnosis - Are we there yet?
Victor Levenson, Associate Professor, Rush University Medical Center
Analysis of methylation in cell-free circulating DNA in blood holds significant promise for non-invasive detection of various diseases. Its potential has been conclusively demonstrated for neoplastic, neurodegenerative, and other diseases, although every time healthy controls have been compared to disease. As the result, the question remains – What exactly is detected? Does every disease have its own DNA methylation signature or are signatures organ-specific, and for each organ inflammation or benign lesions produce the same signatures as cancer? So far, accumulated data argue for disease-specific DNA methylation. DNA methylation patterns are very different in plasma of patients with chronic pancreatitis or adenocarcinoma of the pancreas, suggesting that inflammatory process has its own unique pattern. Similarly, plasma patterns from patients with benign ovarian lesions are different from those from patients with ovarian cancer. If these findings are confirmed for other diseases, analysis of plasma DNA methylation may provide a universal platform for minimally invasive differential diagnosis of different diseases.
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9:30
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TBA
Enal Razvi
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10:00
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Coffee and Networking in Exhibition Hall
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10:45
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Histone Methylation: The Missing Link Between Chromatin and DNA Repair
Brenden Price, Assistant Professor, Dana-Farber Cancer Institute
DNA repair requires significant alteration in chromatin architecture. Here, we discuss a crucial role for the histone modification H3K9me3 in co-ordinating the activation of DNA damage response pathways, and explain how histone methylation controls activation of the Tip60 acetyltransferase.
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11:15
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TBA
Axel Schumacher, Project Leader, The Krembil Epigenomics Laboratory
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11:45
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Resetting the Epigenetic Code by Histone Deacetylase Inhibition Leads to Abrogation of Autoimmune Diabetes via Differential Regulation of Cytokines
Sundararajan Jayaraman, Associate Professor, University of Illinois
Epigenetic modifications of the genome can prevent the occurrence of autoimmune diabetes in mice. This is associated with differential modulation of cytokine gene expression.
We found that treatment with a histone deacetylase inhibitor prevented the occurrence of overt type 1 diabetes in non-obese diabetic mice. Drug treatment induced transient histone acetylation in the pancreas and spleen, abrogated inflammation of the islets, and preserved ß cell function without numerically altering dendritic cells and T regulatory cells in the spleen. The expression of IFN-? mRNA and protein levels was significantly enhanced in stimulated splenocytes derived from cured mice while TNF-a mRNA but not protein expression was reduced in non-T cells. The expression of IL-4, IL-17, IL-18 and iNOS was not modulated by drug treatment. These results suggest that epigenetic modulation of the genome can lead to protection against autoimmune diabetes via differential cytokine expression.
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12:15
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Technology Spotlight
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12:30
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Lunch
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1:30
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Poster Viewing Session 1
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2:00
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Searching the PDB for Novel Readers of Methyl Marks
Matthieu Schapira, Associate Professor, University of Toronto
The majority of known methyl-lysine readers (PHD, Chromo, MBT, Tudor, PWWP domains and Ankyrin repeats) possess an aromatic cage composed of two or more Phe, Tyr or Trp residues that may additionally include an Asp or Glu residue. A computer algorithm was specifically developed to screen all experimental structures of human proteins in the Protein Databank for solvent-accessible aromatic cages. The genes identified include known and novel putative readers of the histone code that may be involved in epigenetic signaling. Ligands co-crystallized to diverse aromatic cages indicate specific chemotypes that may be exploited by medicinal chemists to develop inhibitors against readers of methyl marks.
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2:30
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Development of Diabetic Complications as a Result of Prior Poor Glycemic Control are Mediated by Persistent Activating Epigenetic Changes of Methyl-writing and -erasing Enzymes
Assam El-Osta, Head of Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute
Defining the molecular events that lead to a phenomenon described as “metabolic memory” which is associated with endothelial cell dysfunction will provide critical insights into the interpretation of persistent epigenetic gene-activating events.
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3:00
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Coffee and Networking in Exhibition Hall
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3:45
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Dynamic DNA Methylation Programs Persistent Adverse Effects of Early-life Stress
Chris Murgatroyd, Post-Doc, Max-Planck Institute of Psychiatry
Early-life stress (ELS) has long lasting effects on the brain. Maternal separation in mice persistently alters the offspring's hormonal responses to stress; this included elevated vasopressin (AVP) in the hypothalamus and treatment with an receptor antagonist was able to reverse the effects of early-life stress. The altered AVP expression was associated with sustained DNA hypomethylation of a region in the AVP enhancer that serves as a binding site for the methyl-CpG binding protein 2 (MeCP2). Neuronal activity was able to control the ability of MeCP2 to regulate transcription of the AVP gene and induce epigenetic marking. Thus, ELS can dynamically control DNA methylation in postmitotic neurons to generate stable changes in AVP expression that trigger neuroendocrine and behavioral alterations which are frequent features in depression.
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4:15
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Epigenomic Diversity of Colorectal Cancer Indicated by LINE-1 Methylation in a Database of 869 Tumors
Shuji Ogino, Associate Professor of Pathology, Harvard Medical School
Colorectal cancer is not a single disease, but a heterogenous group of diseases at the molecular level. Our data indicate diversity of its epigenomic status, implying the necessity of considering its epigenomic heterogeneity when developing targeted therapy.
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4:45
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Drinks Reception
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Day 2
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9:00
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Keynote Presentation:
Rudolf Jaenisch, Professor, Whitehead Institute for Biomedical Research
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9:30
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TBA
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10:00
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Coffee and Networking in Exhibition Hall
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10:45
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ATRX Partners with Cohesin and MeCP2 and Contributes to Developmental Silencing of Imprinted Genes in the Brain
Nathalie Berube, Assistant Professor, University of Western Ontario and Children's Health Research Institute
Human developmental disorders caused by chromatin dysfunction often display overlapping clinical manifestations, such as cognitive deficits, but the underlying molecular links are poorly defined. Here we show that ATRX, MeCP2 and cohesin, chromatin regulators implicated in ATR-X, RTT and CdLS syndromes, respectively, interact in the brain and co-localize at the H19 imprinting control region (H19 ICR) with preferential binding on the maternal allele. Importantly, we show that ATRX loss results in altered enrichment of cohesin, CTCF and of histone modifications at the H19 ICR, without affecting DNA methylation on the paternal allele. ATRX was also required for normal occupancy of cohesin, CTCF and MeCP2 at a second imprinting control region within the Gtl2/Dlk1 imprinted domain. Finally, we show that loss of ATRX interferes with the postnatal silencing of the maternal H19 gene along with a larger network of imprinted genes. We propose that ATRX, cohesin and MeCP2 cooperate in the developmental silencing a subset of imprinted genes in the postnatal brain.
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11:15
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The Effect of EBV Transformation on Genome-wide Methylation Pattern
Karolina Aberg, Assistant Professor, Virginia Commonwealth University
The goal of this study is to evaluate the effect of the Epstein-Barr virus (EBV) transformation on methylation patterns in human lymphocytes. This will shed light on whether (whole-genome) methylation studies can be performed using samples from the increasing number of repositories that often create cell lines to be able to continuously supply DNA for multiple investigations. We used a genome-wide approach to investigating DNA extracted from whole blood, in duplicates, and EBV transformed DNA from 10 unrelated individuals. Genomic DNA was fragmented and enriched for methylated regions using MethylMiner, which captures DNA fragments that contain methylated CpG sites. The methylation-enriched fraction from each sample (N=30) was hybridized to 45 million probes on the Affymetrix GeneChip® Human Tiling 2.0R Array Set. Preliminary results indicate that the correlation between the two samples extracted from whole blood and the EBV transformed DNA is high (0.88 – 0.98) meaning that the transformation largely preserve the rank of the probe intensities. However, if we use a mixture modeling approach that enables us to study only the methylated regions, there are clear indications that the EBV transformation disturbs the methylation patterns of individual subjects.
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11:45
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Imprinted Genes Show Upregulation Similar to Dosage Compensation of X-linked Genes
Ismail Zaitoun, Post-Doc, University of Wisconsin-Madison
Genomic imprinting is a parent-of-origin-specific monoallelic expression of a subset of genes in placental mammals. Imprinted genes, which belong to families with different biological functions, control growth and development in a dose-dependent manner and their aberrant expression is associated with defects in development, growth, and behavior. Imprinted genes show allele-specific histone modification patterns; silenced alleles are bound by suppressive modifications, while expressed alleles are associated with permissive histone modifications, suggesting that imprinted genes would show upregulation in gene expression. To investigate this in mice, we calculated the intensity of expression of 59 imprinted genes relative to the rest of the genome by analyzing microarray data. Quantitative real-time PCR (qPCR) was performed to confirm microarray results. Expression of imprinted genes was found to be upregulated in a wide spectrum of adult and embryonic mouse tissue types. Consistent with their functions in growth and development, imprinted genes were found to be highly expressed in extraembryonic tissues and progressively upregulated during early embryonic development. In conclusion, upregulation of imprinted genes found in this study is similar to the dosage compensation (twofold upregulation) recently reported for X-linked genes.
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12:15
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Technology Spotlight
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12:30
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Lunch
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1:30
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Poster Viewing Session 1
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2:00
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TBA
Claes Wahlestedt, Professor, Director of Neuroscience Discovery, The Scripps Research Institute
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2:30
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Decreased Histone-acetylation Status and Increased HDAC Activity Characterize Waldenstrom’s Macroglobulinemia Tumor Cells
Aldo Roccaro, Instructor in Medicine, Harvard Medical School, Dana-Farber Cancer Institute
Epigenetic regulation of gene expression, including histone acetylation, is commonly deregulated in many malignancies leading to aberrant transcription, but histone acetylation status in low grade lymphoplasmacytic lymhoma, such as Waldenstrom’s Macroglobulinemia (WM) has not been evaluated yet.
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3:00
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Coffee and Networking in Exhibition Hall
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3:45
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Epigenome Sequencing comes of age in Development, Differentiation and Diseases Mechanism Researches
Li Ling, Project Leader, BGI
We have generated the first human diploid methylome profile in a blood monocyte cell. In our study, the first high resolution human DNA methylation profile map was generated, which was determined by 20X coverage genome-wide resequencing after bisulfate treatment. The study performed herein not only provides a comprehensive methods for detailed understanding of epigenetic regulation mechanisms, but also serves as a catalyst for future studies of the epigenetic mechanisms that regulates development, differentiation and immune regulation mechanisms.
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4:15
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Ewing's Sarcoma Family of Tumors (ESFT): A Case of Oncogene-mediated Epigenetic-addiction?
Idriss Bennani-Baiti, Children's Cancer Research Institute Associate Investigator
Ewing's sarcoma offers a good model to investigating the epigenetic bases of cancer. We present our findings on several histone-modifying enzymes such as Aurora-B, BRCA1, EZH2, MLLT3, p300, and jumonji proteins that contribute to the oncogenic phenotype of many cancers.
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4:45
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Close of Conference
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