Third International
Epigenomics & Sequencing 2009
Meeting on ‘Chromatin Methylation to Disease Biology & Theranostics’
July 13-14, 2009

The Joseph B. Martin Conference Center at Harvard Medical School
77 Avenue Louis Pasteur, Boston, MA 02115, USA

“A Unique Theme to Combine Chromatin biology and Diseases with Sequencing Chemistry”

Scientific Organizing Committee:

Krishnarao Appasani, PhD., MBA (Chair)
Founder & CEO
GeneExpression Systems, Inc. Waltham, MA USA

Laurie Jackson-Grusby, Ph.D.
Assistant Professor of Pathology, Children's Hospital, Harvard Medical School, Boston, MA

Michelle Lyles, Ph.D.
Vice President, Marketing and Sales
febit, inc. Lexington, MA, USA 

Shuji Ogino, MD., PhD.
Associate Professor & Associate Pathologist
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Topics or Highlights of the Meeting:

Mechanisms of Chromatin in gene regulation
Nuclear dynamics and Methylation Assays
Parental imprinting and Histone Deacetylation inhibitors as drugs
Epigenetic re-programming in stem cells
Cutting-edge sequencing technology; Epigenome Sequencing
Epigenetic regulatory processes in diseases & environment
PharmacoEpigenomics

AGENDA/SPEAKERS Click Here For Agenda

Monday, July 13, 2009

7:30 A.M: Registration Open
8.30 AM – 6.00 PM Scientific Sessions

Tuesday, July 14, 2009

7:30 A.M: Registration Open
8.00 AM – 5.00 PM Scientific Sessions
5:00 PM Meeting Concludes

Confirmed Speakers:

Alex Meissner, PhD. Keynote Speaker Epigenomics-2009 Young Innovator Award Winner Assistant Professor of Stem Cell and Regenerative Biology Harvard University & Associate member of the Broad Institute Principal Faculty at Harvard Stem Cell Institute Cambridge, MA, USA Title:Epigenomics and Cellular States

	Shuji Ogino, MD., PhD. Associate Pathologist Department of Pathology, Brigham and Women's Hospital Associate Professor of Pathology, Harvard Medical School Boston, MA, 02115, USA Title: Significance of Epigenomic Alterations in Colorectal Cancer
	Laurie Jackson-Grusby, Ph.D. Assistant Professor of Pathology Harvard Medical School Children's Hospital Boston Boston, MA 02115, USA Title:TBA
	Peter J. Park, Ph.D. Assistant Professor of Pediatrics & Harvard Medical School Harvard-Partners Center for Genetics & Genomics Boston, MA, USA Title: Analysis of ChIP-sequencing experiments and its application to dosage compensation in Drosophila
	Elizaveta V. Benevolenskaya, PhD. Assistant Professor of Biochemistry University of Illinois at Chicago Chicago, IL, USA Title: Transcriptional program supported by the RBP2 histone demethylase in cancer
	Shaun Mahony, PhD. Postdoctoral Research Associate Computer Science & Artificial Intelligence Laboratory Massachusetts Institute of Technology Cambridge, MA, USA Title: TBA
	John F. Thompson, PhD. Senior Director, Genomic Research Helicos BioScience Corporation Cambridge, MA, USA Title: Amplification-free Single Molecule Sequencing of Epigenomic Modifications
	Hiroto Kouji The University of Tokyo Tokyo, Japan Title: Transcription of mRNA-type long non-coding RNAs (mlonRNAs) disrupts chromatin array
	Victoria (Fatemeh) G. Haghighi, Ph.D. Assistant Professor of Neuroscience Columbia University & New York State Psychiatric Institute New York, NY, USA Title: Whole Genome DNA Methylation Profiling of Major Depression
	Nick Wong, PhD. Postdoctoral Fellow of Developmental Epigenetics  Murdoch Childrens Research Institute The University of Melbourne & Royal Children’s Hospital Victoria, Australia Title: DNA Methylation analysis using archived blood spot and bone marrow samples
	Stephen Turner, PhD. Founder & Chief Technology Officer Pacific Biosciences, Inc. Menlo Park, CA, USA Title:
	Michael Green, PhD., MD. Professor University of Massachusetts Medical School Program in Gene Function and Expression Worcester, MA, USA Title: Dissecting Epigenetic Silencing Mechanisms Using Genome-Wide RNA Interference Screens
	Terrence S. Furey, PhD. Assistant Professor of Computational Biology Duke University Institute for Genome Sciences and Policy (IGSP) Durham, NC, USA Title: High resolution mapping studies of chromatin
	Myles Brown, M.D. Professor of Medicine & Chief of Mol. & Cellular Oncology Harvard Medical School & Dana-Farber Cancer Institute Boston, MA 02115, USA Title: TBA
	Atsushi Kaneda, MD, PhD. Associate Professor of Genome Science The University of Tokyo Tokyo, Japan Title: Epigenotyping by quantitative DNA methylation analysis revealed three epigenotypes of colorectal cancer
	Gavin Meredith, PhD. Senior Scientist of Epigenetics Life Technologies, Inc. Carlsbad, CA, USA Title: MBD-based Enrichment of Methylated DNA for High-Throughput Sequencing
	Edith Pfister PhD Student in the Lab of Dr. Neil Aronin 364 Plantation St, LRB 270C Worcester, MA 01605, USA Title: RNAi targeting of single nucleotide polymorphisms in the Huntingtin gene
	Pardis Sabeti, M.D. D.Phil. Assistant Professor of Organismic & Evolutionary Biology Center for Systems Biology Harvard University Cambridge, MA, USA Title: TBA
	Charles Lee, Ph.D., FACMG Associate Professor of Pathology Harvard Medical School & Brigham and Women's Hospital Associate Faculty Member, MIT Broad Institute Boston, MA, USA Title: TBA
	Jin Billy Li, PhD. Postdoctoral fellow in Genetics Harvard Medical School Boston, MA , USA Title: Targeted Sequencing of Human Genomes, Transcriptomes and Methylomes
	Kornelia Polyak, M.D.,Ph.D. Associate Professor of Medicine Dana-Farber Cancer Institute Harvard Medical School Boston, MA, USA
	Steve Carroll, PhD. Broad Inst. Of MIT and Harvard Cambridge, MA, USA.
	Emelia J. Benjamin, MD. Professor of Medicine and Epidemiology Boston Univ Schools of Medicine and Public Health Framingham, MA, USA Title: Genetics of Atrial fibrillation focusing on SNP analysis.
	Andreas Tobler, PhD. Staff Scientist Life Technologies, Inc. Foster City, CA, USA Title: TaqMan Copy Number Assays - New Tool for Validating CNVs Related to Human Diseases
	Dr. Claes Wadelius Professor of Genetics & Pathology Uppsala University Uppsala, Sweden Title: A new Darwinian force with an epigenetic twist
	Cassandra L. Smith, PhD. Professor Biomolecular Engineering College of Engineering, Boston University Boston, Mass 02215, USA Title: Schizophrenia: The nature and nurture of a common disease
	Brian Egan PhD. Program Director Genpathway, Inc. San Diego CA 92121, USA Title: Genome-wide ChIP based studies of gene regulation
	Han Joo Lee, DPhil. Field Applications Scientist febit, inc. Lexington, MA, USA  Title: The Power to Detect: HybSelect™ for Targeted Sequence Capture
	Sungwhan An, P.hD. CEO/CSO Genomictee, Inc. Yuseong Daejeon, South Korea Title: High throughput profiling of DNA methylation patterns in colon cancer and biomarker development for early detection and prognosis

Will be included more from academia, pharma and biotech.....

Exhibitors are welcome to reserve their booth space early!

Please contact if you are interested in speaking in the scientific or Technology workshops of this meeting.

GeneExpression Systems, Inc.
P.O. Box 540170
Waltham, MA 02454 USA
Tel: (781) 891-8181
Fax: (781) 891-8234
E-mail: Genexpsys@expressgenes.com
www.expressgenes.com

Poster Abstract Submission by May 30, 2009

ALL ABSTRACTS

Transcription of mRNA-type long non-coding RNAs (mlonRNAs) disrupts chromatin array
Dr. Hiroto Kouji, Kyoto University Graduate School of Medicine, Dept. of Radiation Genetics, Kyoto, 606-8501, Japan

Kouji Hirota & Kunihiro Ohta

Eukaryotic transcriptome analyses have revealed the presence of a huge number of mRNA-type non-coding RNAs (ncRNAs), but little is know bout their function. We have recently demonstrated that cascade of RNA polymerase II (RNAPII)-mediated transcription initiation of such mRNA-type long ncRNAs (mlonRNA) results in stepwise disruption of local chromatin structure at the fission yeast Schizosaccharomyces pombe fbp1 locus during transcriptional activation upon glucose derepression. Similar transition of RNA transcripts coupled with local chromatin alteration is observed meiotically in the fission yeast recombination hotspot ade6-M26. Here, we hypothesize that RNAPII transcription of mlonRNA disrupts chromatin array collaborating with histone acetylation mechanism.

Amplification-free Single Molecule Sequencing of Epigenomic
Modifications
John F. Thompson, PhD., Senior Director, Genomic Research, Helicos BioScience Corporation, Cambridge, MA, USA

Epigenomic modifications on human DNA have become increasingly associated with important disease and developmental processes as tools have advanced, allowing examination on a genome-wide basis. The ability to accurately quantitate such signals is critical but much of that information can be lost with amplification-based approaches due to quantitative biases introduced by amplification of the target DNA or lack of coverage of regions due to base composition. We describe a single molecule sequencing approach that can be used to characterize epigenomic modifications without amplification of DNA and present genome-wide results of its application to mammalian systems.

Whole Genome DNA Methylation Profiling of Major Depression
Victoria (Fatemeh) G. Haghighi, Ph.D., Assistant Professor of Neuroscience (in Psychiatry) Columbia University Department of Psychiatry & New York State Psychiatric Institute
New York, NY, USA

Epigenetics may play a role in the etiology of neuropsychiatric disorders, possibly through abnormal genomic DNA and histone methylation patterns that regulate genes involved in brain development or physiology. The aim of the present study is to explore the epigenetic profile of major depressive disorder (MDD). In order to better understand both the wild type genomic DNA methylation patterns and aberrant methylation events that occur in disease states, we have developed a cost-effective, unbiased, whole-genome methylation profiling technique that can assay the methylation state of more than 80% of the CpG sites in the human genome. Using our methodology, which couples advances in next generation sequencing with enzymatic fractionation of DNA by methylation state, we are mapping the methylation at high coverage for MDD cases and matched controls. We also mapped the histone methylation, H3K4me3 patterns in some of the same samples using ChIP-seq. We focused on the prefrontal cortex (PFC) due to converging evidence from neuroimaging and functional studies implicating this region in MDD. In the first genome-wide DNA and histone methylation profiling study of major depression, we identified aberrant methylation at several genes including those involved in CNS function. Subsequent to validation of these differentially methylated regions on the Sequenom platform, we are expanding our analysis of these regions to a large sample of PFC tissue from 60 controls and MDD cases with comprehensive clinical and toxicological profiles. These DNA methylation abnormalities may have clinical utility as biomarkers, and evaluation of the frequency of these alterations may help identify etiologic factors involved in MDD.

Epigenotyping by quantitative DNA methylation analysis revealed three epigenotypes of colorectal cancer
Atsushi Kaneda, MD, PhD., Associate Professor of Genome Sciences, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

To epigenotype colorectal cancer (CRC) by DNA methylation comprehensively, we performed methylated DNA immunoprecipitation (MeDIP)-chip analysis of CRC line HCT116. Among 3,814 genes with promoter methylation identified, new methylation markers were selected, using expression array data of normal colon and HCT116 treated with/without 5-aza-2¢-deoxycytidine/Trichostatin A. Methylation levels of these markers in clinical CRC samples were analyzed quantitatively using MALDI-TOF mass spectrometry. By unsupervised hierarchial clustering, CRC was clustered into high-, intermediate-, and low-methylation epigenotypes, which correlated with BRAF mutation, with KRAS mutation and worse prognosis, and with p53 immunostaining(+), respectively. These clusters may suggest different carcinogenesis and prognosis of CRC.

High throughput profiling of DNA methylation patterns in colon cancer and biomarker development for early detection and prognosis
Sungwhan An, P.hD. CEO, Genomictee, Inc., Daejeon, South Korea

It has become evident that abnormal changes in DNA methylation (meDNA) occur during tumorigenesis. Accordingly, defining profiles of altered methylation pattern could be useful for developing methylation biomarkers for early detection and stratification of cancers. We established a method for scanning genome for methylation status of CpG sites utilizing the binding property of engineered methyl-DNA binding polypeptide to meDNA for isolation and CpG-microarray(244K probes), namely Methyl DNA Isolation Assay(MeDIA)-coupled CpG-microarray analysis. With this, we fully described the relative genome-wide methylation patterns in primary tumor and paired non-tumor tissues of 12 patients with different stages of colon cancers (half of them developed disease-recurrence within 3 years) and 2 normal tissues of healthy individuals over common reference DNA as a role of internal control. Methylation patterns was discern enough to distinguish primary tumor from non-tumor tissues which was closely grouped to normal tissues by unsupervised hierarchical clustering with entire data passed a given criteria of filtering. With Welch ANOVA (FDR,0.01), over 400 methylation sites in regulatory regions (2kb upstream to 0.5kb downstream of transcription start site) showed differential methylation patterns between tumor and non-tumor tissues with similar hyper- and hypomethylation. Furthermore, Welch ANOVA and Fisher’s Exact tests in the search of significant differences of DNA methylation sites associated with recurrence and disease free among tumors selected 50 methylation targets and which yielded very good classification results when evaluated by hierarchical clustering and PCA. Validation by pyrosequencing-based methylation assay and reproducibility test of 50-predictor of recurrence in independent study are undergoing. Possibility of early detection in non-invasively collected specimens and prognosis of predicting disease-recurrence of colon cancer will be addressed in this presentation.

Transcriptional program supported by the RBP2 histone demethylase in cancer
Elizaveta V. Benevolenskaya, PhD., Assistant Professor of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA

RBP2 is a member of the KDM5 protein family that has been recently identified as histone demethylases specific for trimethylated and dimethylated lysine 4 of histone H3 (H3K4me3/me2). RBP2 has single orthologs in C. elegans, Drosophila, and zebrafish, that are known to be critical developmental regulators, and each protein can perform a JmjC domain-driven demethylase reaction on H3K4. We used integrated genomic approaches to study transcriptional regulation by RBP2. We described that RBP2 target genes are separated into two functionally distinct classes: differentiation-independent and differentiation-dependent genes. These classes display characteristic patterns of upregulation in human tumors.

High Resolution Mapping Studies of Chromatin
Terrence S. Furey, PhD., Assistant Professor of Computational Biology, Duke University, Institute for Genome Sciences and Policy (IGSP)
Durham, NC, USA

Terrence Furey1, Alan Boyle1, Lingyun Song1, Yoichiro Shibata1, Paul Giresi2, Linda Grasfeder2, Daniel McKay2, Damian Keefe3, Stefan Graf3, Zheng Liu4, Ryan McDaniell4, Bum-Kyu Lee4, Paul Flicek3, Ewan Birney3, Vishy Iyer4, Jason Lieb2, Gregory Crawford1

1Institute for Genome Sciences and Policy (IGSP), Duke University, Durham, NC
2University of North Carolina at Chapel Hill, Chapel Hill, NC
3European Bioinformatics Institute, Hinxton, Cambridge, UK
4University of Texas at Austin, Austin, TX

Identifying and characterizing gene regulatory elements across the human genome are critical to furthering our understanding of both transcriptional regulation in general and more specifically its relationship to chromatin structure. We have developed a high-throughput assay, DNase-Seq, that measures DNaseI hypersensitivity (HS) genome-wide identifying regions of open chromatin. This assay generates DNA libraries enriched for short sequences from primarily nucleosome free regions that are then sequenced using Illumina/Solexa GAII sequencers. DNaseI hypersensitive (HS) sites are bound by proteins with enhancer, silencer, and insulator functions among others. Chromatin maps have been or are being created in a diverse collection of cell types, primarily human but also chimp, macaque, and mouse cells. These will allow us to identify and characterize functional elements that are ubiquitous, cell-type specific, evolutionarily conserved, and evolutionarily distinct.

Global Analysis of cis-regulatory SNPS in Human Cells
Tomi Pastinen, MD., PhD., Assistant Professor of Human Genetics and Medical Genetics
& Canada Research Chair in Human Genomics, McGill University and Genome Quebec
Innovation Centre, Montreal, Quebec, Canada

The expanding lists of functional elements in the genome and disease links with non-coding variants call for hypothesis-free assessment of regulatory variation. We interrogate cis-acting components of expression variation using allelic expression (AE) in population panels of human cells. Cis –regulatory variation discovered directly by genome-wide AE mapping is ~ 10X more common than estimated based on in-direct (cis –eQTL) mapping methods using same sample sizes. The AE associated SNPs explain, an average, 60% of population variance in transcription of associated genes in human lymphoblasts. These large effect sizes provide a straightforward approach for pinpointing causal cis-regulatory SNPs (cis-rSNPs). We show how these resources can be used to identify disease causing SNPs and more generally how the on-going work on builds towards genome-wide collection of common cis-rSNPs based on in vivo differences in transcriptional control.

Analysis of ChIP-sequencing experiments and its application to dosage compensation in Drosophila
Peter J. Park, Ph.D., Assistant Professor of Pediatrics & Associate Director of Bioinformatics, Harvard Medical School, Boston, MA, USA

ChIP-seq combines chromatin immunoprecipitation (ChIP) with next-generation sequencing to identify protein-DNA interactions on a genome-wide scale.  A number of practical issues in analysis of ChIP-seq data will be discussed, including experimental design, detection of binding sites, and determination of whether a sufficient depth of sequencing has been achieved.  Application of ChIP-seq to the study of X-chromosome dosage compensation in Drosophila will be described.

MBD-based Enrichment of Methylated DNA for High-Throughput Sequencing
Gavin Meredith, PhD., Senior Scientist of Epigenetics, Life Technologies, Carlsbad, CA, USA

Sensitive, accurate, and versatile tools for the enrichment of methylated sequences from genomic DNA are needed for cost-effective genome-wide studies.  Data will be presented showing the advantages of using a new MBD/magnetic bead-based system, called MethylMiner™, for methylated DNA enrichment and how enrichment before SOLiD™-based high-throughput sequencing returns genome-wide deep coverage of human and plant CpG-methylomes.  MBD-based enrichment is more sensitive to low densities of CpG methylation than anti-5methyl C antibody, is compatible with input amounts ranging from 5 ng to 50 mg, and permits easy fractionation and elution of the methylated sequences based on CpG density with simple changes in NaCl concentration.

Targeted Sequencing of Human Genomes, Transcriptomes and Methylomes
Jin Billy Li, PhD., Postdoctoral Fellow in the Lab of Dr. George Church, Harvard Medical School, Department of Genetics, Boston, MA, USA

Despite the dropping cost, it is still prohibitively expensive to sequence the whole human genomes, transcriptomes, and methylomes, particularly when the sample size is large.  We developed and optimzed a padlock-based approach to amplify human exomes in a single reaction.  Simultaneous targeting of the same sites in both genomic DNA and cDNA allowed us to identify allele-specific gene expression patterns and hundreds of novel A-to-I RNA editing sites.  Because of the near 100% specificity, we extended our technology to bisulfite converted human genomic DNA, and were able to accurately measure cytosine methylation level at thousands of CpG loci simultaneously.

DNA Methylation analysis using archived blood spot and bone marrow samples
Nick Wong, PhD., Postdoctoral Fellow of Developmental Epigenetics, Murdoch Children’s Research Institute, The University of Melbourne, Victoria, Australia

Bisulfite-mediated DNA methylation analysis typically requires significant amounts of genomic DNA from collected biospecimens. This requirement has precluded the use of retrospective biospecimen collections such as Guthrie blood spot and bone marrow aspirate smears on microscope slides for DNA methylation interrogation. Here, we have investigated the feasibility of analysing DNA methylation from archived blood spots, determined an optimal method for DNA extraction and bisulfite conversion for DNA methylation analysis by sequencing and SEQUENOM MassArray EpiTYPER chemistry. We have also performed genome-wide and loci-specific DNA methylation analysis on archived bone marrow aspirate smears from leukaemia patients and demonstrate that it is indeed possible to utilize archived biospecimens as viable source of genomic DNA for DNA methylation analysis.

Epigenomics and Cellular States
Alex Meissner, PhD., Assistant Professor of Stem Cell and Regenerative Biology
Harvard University, Principal Faculty at Harvard Stem Cell Institute, Associate member of the Broad Institute, Cambridge, MA, USA

Pluripotent stem cells can give rise to all cell types in the body and have therefore enormous potential for regenerative medicine, and provide a powerful tool for studies in developmental biology and pharmacology. Recent advances in transforming somatic cells directly into pluripotent (induced pluripotent stem: iPS) cells provide an attractive avenue for generating patient-specific stem cells. However, a notable variation in the differentiation potential of many human ES cell lines has been described. The cause is unknown and likely explanations point towards either genetic and/or epigenetic alterations. Many epigenetic alterations observed in cell culture are similar to changes frequently observed in cancer. I will highlight recent technological advances to map epigenetic marks and how these maps advance our understanding of normal development and cellular states in general.

The Power to Detect: HybSelect™ for Targeted Sequence Capture
Han Joo Lee, DPhil., Field Applications Scientist, febit, inc., Lexington, MA, USA 

The proliferation of NGS platforms has increased DNA sequencing throughput by orders of magnitude, however, it still takes months and several hundreds of thousands of dollars to finish a typical mammalian-sized genome at a reasonable depth of coverage. Certain “high value” regions of the genome have been associated with certain disease states, phenotypic traits, or responses to drug treatment or other environmental stimuli. Targeted re-sequencing of genomes can identify variants faster and at a much lower cost than whole genomes sequencing. Genomic hot-spots ranging between tens and thousands of kilobases are excellent targets for HybSelect, a new automated microfluidic solution for sequence-specific capture from febit. Integrated HybSelect automation allows walk-away convenience and only requires 30 minutes of hands on time, offering the simplest targeted sequence capture method available.

Schizophrenia: The nature and nurture of a common disease
Cassandra L. Smith, PhD., Professor Biomolecular Engineering, College of Engineering, Boston University, Boston, MA, USA

Complex diseases like schizophrenia are linked both to genetic and to environmental factors. However, no single or small number of genetic and/or environmental factors account for the majority of illness. Our research focus is on understanding biochemical aspects of disease that reflect both genetic and environmental factors linked to schizophrenia and other severe neuropsychiatric illnesses. Research by us (and others) has linked schizophrenia to somatic genomic instability, DNA replication, folate metabolism, DNA methylation and paternal age. In addition, disease is linked to malnutrition (including folate deficiencies), viral/parasitic infection, and obstetric complications. Biochemically, the disparate environmental factors appear to converge at the intersection of the folate, methionine, dopamine, choline and trans sulfuration pathways. Mutations in genes in these pathways are linked to schizophrenia. These intersecting pathways require 6 essential nutrients (folate (vitamin B9), cobolamin (vitamin B12), vitamin B6 and methoinine, choline, and are required for the production of the S-adenosyl methionine (SAM: the universal methyl donor), purines, and dTTP, glutathione (the primary intracellular antioxidant), de novo synthesis of glycine, cysteine, and resynthesis of methionine. More than 100 methyl transferases use SAM in vivo including enzymes linked to DNA and histone methylases, dopamine metabolism and schizophrenia. Oxidative stress will influence the production of SAM as well as DNA replication. The intersecting pathways are closely linked at the metabolic level and are coordinately regulated in a complex manner. Severe perturbations to the balance of the intersecting will be lethal to a cell. However, less severe perturbations will have multiple and complex cellular effects.

Genome-wide ChIP based studies of gene regulation
Brian Egan, PhD., Program Director, Genpathway, Inc., San Diego, CA, USA

Chromatin immunoprecipitation is a powerful technique for delineating genome-wide patterns of transcription, transcription factor binding and histone modifications. A related technique using purified DNA and anti-5 methyl-cytosine antibodies can reveal genome-wide DNA methylation patters. An overview of these techniques will be presented as well as example data sets relevant to biomarker discovery and the mechanistic basis of drug response. Additionally, novel insights into gene regulation from studies that integrate data sets from multiple platforms, such as whole-genome ChIP and RNA expression data, will be presented.

Significance of Epigenomic Changes in Colorectal Cancer
Shuji Ogino, MD., PhD., Associate Pathologist at Brigham and Women's Hospital & Associate Professor of Pathology, Harvard Medical School, Boston, MA, USA

Epigenomic changes are important mechanisms in carcinogenesis.  In colorectal neoplasia pathways, promoter CpG island methylation and global DNA hypomethylation play significant roles.  In particular, the CpG island methylator phenotype (CIMP) has been established as a distinct phenomenon in colorectal cancer.  Utilizing two large prospective cohort studies, we have been examining the relations between epigenomic changes, dietary and lifestyle exposures, germline genotypes, somatic genetic events, and patient survival.  We have found that epigenomic alterations can be biomarkers for the elucidation of carcinogenic process as well as for predicting clinical outcome.  

Dissecting Epigenetic Silencing Mechanisms Using Genome-Wide RNA Interference Screens
Michael Green, PhD., MD., Professor of Molecular Medicine, University of Massachusetts Medical School, Program in Gene Function and Expression, Worcester, MA, USA

Inactivation of tumor suppressor genes critical for cancer development frequently occurs by epigenetic silencing. Many aspects of epigenetic silencing—such as how specific genes are targeted and the identity of the factors required to recruit DNA methyltransferases to promoters—are not well understood. To gain a better understanding of the mechanistic basis of epigenetic silencing, we have performed genome-wide RNA interference screens to identify factors and pathways required for epigenetic silencing. The results of our studies have shed light on the mechanisms by which genes are epigenetically silenced, and have revealed new genes and regulatory pathways involved in cancer development.