Cambridge Healthtech Institute’s Second Annual  

Epigenomics in Disease  

Above the Genome - Underlying Disease

February 16-18, 2015 | Moscone North Convention Center | San Francisco, CA
Part of the 22nd Annual Molecular Medicine Tri-Conference

 

It is now universally recognized that dysregulation of the regulatory layers above the genome— namely the epigenome — produces aberrant gene expression leading to disease. With advances in sequencing technologies, drivers and mechanisms of disease initiation are being unraveled, and a more holistic view of the interplay between the genome and a very active epigenome is taking shape. Importantly, these findings form inextricable causal links between our underlying genome, the regulatory epigenome, and the functional (disease) consequence stemming from both.

The Epigenomics in Disease meeting will gather leading researchers advancing our understanding of the epigenetic contributors to disease, explore novel approaches and technologies for interrogation, and discuss the utilization of epigenomic analysis for personalized diagnostics and treatment.


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Monday, February 16

10:30 am Conference Program Registration


INTERROGATING DISEASE (EPI)GENOMES

11:50 Chairperson’s Opening Remarks

Susan Clark, Ph.D., Professor & Director, Epigenomics Centre, The Kinghorn Cancer Centre, Garvan Institute of Medical Research


12:00 pm KEYNOTE PRESENTATION: Regulatory Genomics and Epigenomics of Complex Disease

Manolis Kellis, Ph.D., Professor, Computer Science, MIT; Director, Computational Biology Group, Computer Science and Artificial Intelligence Lab (CSAIL), Broad Institute of MIT and Harvard


12:30 Epigenome-Wide Landscape of Melanoma Progression to Brain Metastasis

David Hoon, Ph.D., Chief, Scientific Intelligence, Director, Molecular Oncology, John Wayne Cancer Institute

Brain metastases (BM) represent the deadliest complication of cutaneous melanoma and other tumors types. Even though the epigenomic aberrations in different primary tumors are well studied, their influence on tumor progression to BM still remains largely unexplored. By integrating genome-wide DNA methylation, gene expression, copy number variation, single nucleotide polymorphisms, DNase I hypersensitive sites, and chromatin immunoprecipitation analyses, we identified epigenome-wide alterations that contribute to the melanoma progression to BM. Interestingly, progressive DNA demethylation affected low-CpG density regions while an increment on DNA methylation level was evidenced in high-CpG density regions. BM-specific partially methylated domains (PMDs) were enriched in genes affecting brain developmental processes. An enhancer controlling the expression of homeobox D9 gene (HOXD9) was specifically inactivated during melanoma progression to BM. Also, BMs presented substantial inter-patient DNA methylation heterogeneity. Patients with a high number of aberrantly methylated tumor-related genes (TRGs) presented a mutual exclusivity with BMs containing deletions on the CDKN2A/B loci a frequent event in melanoma. Additionally, epigenomic deregulation on spliceosome factors were characterized in the progression from primary melanoma to BM. These alterations contribute to a splicing reprogramming which enhances the brain colonization potential of melanoma cells. I will discuss the key role of epigenomic aberrations on the extraordinarily dynamic gene expression reprogramming of melanoma progression to BM.

1:00 Session Break

1:15 Luncheon Presentations (Sponsorship Opportunities Available) or Lunch on Your Own

2:15 Session Break


EPIGENETICs IN NEUROPATHOGENESIS

2:30 Chairperson’s Remarks

Joseph Costello, Ph.D., Professor in Residence, Neurological Surgery; Director, Epigenetics Division, Cell Cycling and Signaling Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

2:40 Co-Dependency of the Genome and Epigenome during Tumor Evolution

Joseph Costello, Ph.D., Professor in Residence, Neurological Surgery; Director, Epigenetics Division, Cell Cycling and Signaling Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

The clonal evolution of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast, tumor epigenetic states are reversible and sensitive to the tumor microenvironment, presumably precluding the use of epigenetics to discover the clonal and sub-clonal evolution of tumors. We recently used mutation patterns to learn how low grade gliomas evolve over time, and also discovered that temozolomide treatment of LGG is associated with TMZ-induced hypermutation and malignant progression to GBM. Here we examined the spatial and temporal dynamics of DNA methylation in our clinically and genetically characterized cohort of IDH1-mutant low-grade gliomas and their patient-matched recurrences. We constructed phylogenetic and phyloepigenetic relationships among co-evolving tumor cell populations. Despite the plasticity of tumor epigenetic states, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations in the same patients.

3:10 Epigenetic “Addiction” in Pediatric Brain Tumors: A Tale of a Histone Tail

Nada Jabado, M.D., Ph.D., Associate Professor, Pediatrics; Associate Member, Human Genetics, Oncology and Experimental Medicine, McGill University

Brain tumors are the leading cause of cancer-related mortality and morbidity in the pediatric years. We and others identified a new molecular mechanism driving pediatric high grade astrocytomas, namely recurrent somatic driver mutations in the tail of histone 3 variants (H3.3 and H3.1) leading to amino acid substitutions at key residues, namely lysine (K) 27 (K27M) and 36 (G34R or G34V). We further showed H3.3G34V/R and H3.3/H3.1K27M mutations are tightly correlated with a distinct global DNA methylation pattern and that each mutation has neuroanatomical and age specificities and distinct need for combined genetic alterations, namely mutations in ATRX and TP53 genes and growth factor receptors including ACVR1 and PDGFRA. H3 variants mutations alter chromatin structure affecting specific molecular pathways which lead to gliomagenesis, and each mutation induces a distinct change in chromatin structure and downstream events that needs characterizing independently. Importantly, the type, timing and spatial clustering of these molecular alterations provide a better understanding of the pathogenesis of the respective brain tumor they target and critical markers for therapy that will help refine pathological grading.

3:40 Genetic-Epigenetic Interactions in Cis and Trans: Relevance to the Human Brain and Immune System

Benjamin Tycko, M.D., Ph.D., Professor, Pathology and Cell Biology, Institute for Cancer Genetics & Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University

4:10 Sponsored Presentations (Opportunities Available)

4:40 Break and Transition to Plenary Session

5:00 Plenary Session

6:00 Grand Opening Reception in the Exhibit Hall with Poster Viewing

7:30 Close of Day


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Tuesday, February 17

7:00 am Registration and Morning Coffee

8:00 Plenary Session

9:00 Refreshment Break in the Exhibit Hall with Poster Viewing


MECHANISMS UNDERPINNING DISEASE: CHROMATIN DYNAMICS AND LONG-RANGE REGULATORY CONTROL

10:05 Chairperson’s Remarks

David Hoon, Ph.D., Chief, Scientific Intelligence; Director, Molecular Oncology, John Wayne Cancer Institute

10:15 FEATURED PRESENTATION: Epigenome Remodelling and DNA Replication Timing: What are the Implications in Cancer?

Susan Clark, Ph.D., Professor & Director, Epigenomics Centre, The Kinghorn Cancer Centre, Garvan Institute of Medical Research

Epigenetic deregulation is involved in cancer initiation and progression, but the mechanism underpinning these epigenetic alterations, especially during DNA replication is still poorly understood. We previously reported that epigenetic changes could occur over large domains, resulting in concordant gene repression by Long Range Epigenetic Silencing (LRES) and concordant gene activation by Long Range Epigenetic Activation (LREA) of multiple adjacent genes in cancer. By an integrative epigenome-wide sequencing analysis of prostate cancer and normal cells, we found the epigenetic deregulated domains are characterised by an exchange of active (H3K9ac and H3K4me3) chromatin marks, and repressive (H3K9me2 and H3K27me3) marks. Notably, whilst promoter hypomethylation did not often contribute to gene activation, extensive DNA hypermethylation of CpG islands or “CpG island borders” was strongly related to both gene repression and cancer-specific gene activation or a change in promoter usage. Here, I will discuss our latest data to inform the mechanism(s) involved in epigenome remodelling and the spatial and temporal dynamics associated with deregulated domains of the cancer epigenome. These findings have wide ramifications for cancer diagnosis, progression and epigenetic-based gene therapies.

10:45 Linking Histone Recognition to the Epigenetic Inheritance of DNA Methylation

Brian Strahl, Ph.D., Professor & Director, Biochemistry & Biophysics, University of North Carolina School of Medicine

Histone modifications and DNA methylation are two key epigenetic regulators of DNA information in chromatin, controlling chromatin structure and gene activity in mammals in part through the recruitment of effector proteins. We have shown that UHRF1, a DNA- and histone-binding E3 ubiquitin ligase, functions in the DNA methylation program through constitutive multivalent recognition of a heterochromatic signature found on H3. We now show that hemi-methylated DNA recognition by UHRF1 is directly coupled to H3 recognition by this protein. Data will be presented that reveal how these domains are communicating with each other to mediate a highly coordinate histone-DNA binding event in chromatin.

11:15 Remodeling the Remodelers: BAF Complex Structure and Function in Human Malignancy

Cigall Kadoch, Ph.D., Assistant Professor, Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School

Recent genome-wide exon sequencing studies have revealed that over 20% of human cancers bear mutations in the genes encoding subunits of mammalian SWI/SNF (or BAF) ATP-dependent chromatin remodeling complexes, making them the most frequently and broadly mutated chromatin regulator. Our studies focus upon cancers with genomically well-defined BAF complex aberrations, such as synovial sarcoma, malignant rhabdoid tumors, and others to uncover the structural and functional consequences of BAF complex perturbation, and to catalyze the identification of therapeutics for this class of tumors.

11:45 Extensive Variation in Chromatin States across Humans

Maya Kasowski, Ph.D., Fellow, Synder Lab, Genetics, Stanford University

The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. The understanding of normal human variation in chromatin is fundamental to understanding the role of epigenetic variation in disease.

12:15 pm Session Break

12:25 Luncheon Presentations (Sponsorship Opportunities Available) or Lunch on Your Own

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing


TECHNOLOGICAL ADVANCES ENABLING
EPIGENOMIC DISCOVERY

2:00 Chairperson’s Remarks

Ido Amit, Ph.D., Associate Professor, Immunology; Principal Investigator, Laboratory for Immuno-Genomics, Weizmann Institute of Science

2:10 FEATURED PRESENTATION: Shaping the Blood: Lessons from Chromatin and Single Cell RNA Dynamics

Ido Amit, Ph.D., Associate Professor, Immunology; Principal Investigator, Laboratory for Immuno-Genomics, Weizmann Institute of Science

Chromatin modifications are crucial for development, yet little is known about their dynamics during differentiation. Hematopoiesis provides a well-defined model to study chromatin state dynamics; however, technical limitations impede profiling of homogeneous differentiation intermediates. Using a novel high-sensitivity indexing-first chromatin immunoprecipitation approach we profile the dynamics of four chromatin modifications across 16 stages of hematopoietic differentiation. We find that lineage commitment involves de novo establishment of thousands of lineage-specific enhancers. These enhancer repertoire expansions foreshadow transcriptional programs in the differentiated cells. Combining our enhancer catalog with single cell gene expression profiles, we elucidate the transcription factor network controlling chromatin dynamics and lineage specification in hematopoiesis. Together, our results provide a comprehensive model of chromatin dynamics during development.

2:40 Highly Sensitive Methods for Analysis of the “Accessible Genome”

William James Greenleaf, Ph.D., Assistant Professor, Department of Genetics, Stanford University School of Medicine

Eukaryotic genomes are hierarchically packaged into chromatin, and the nature of this packaging plays a central role in gene regulation. We have developed an Assay for Transposase Accessible Chromatin using sequencing (ATAC-seq)— based on direct in vitro transposition of sequencing adapters into native chromatin – as a rapid and sensitive method for integrative, high-resolution epigenomic analysis. With this method, we have investigated the chromatin changes associated with aging in T cells, as well as regulatory variation at the single-cell level.

3:10 Hybridization-Based Epigenotyping Using Methyl Binding Domains for Routine Clinical Analyses

Hadley D. Sikes, Ph.D., Joseph R. Mares Assistant Professor, Chemical Engineering, Massachusetts Institute of Technology

Basic and translational studies suggest that knowledge of the CpG methylation status of particular promoters has utility for predicting response to therapy and perhaps for diagnosis of several cancers. However, the techniques used to make these discoveries are not well suited for routine use in the clinical setting. We are quantitatively investigating hybridization-based epigenotyping using methyl binding domain proteins as an approach that eliminates bisulfite treatment steps and may be well suited for everyday use in pathology labs.

3:40 Sponsored Presentations (Opportunities Available)

4:10 Mardi Gras Celebration in the Exhibit Hall with Poster Viewing

5:00 Breakout Discussions in the Exhibit Hall

This interactive session provides attendees an opportunity to choose a specific discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.

Detailed Epigenomic Profiling of Different Cell Types within Organs

Ite A. Laird-Offringa, Ph.D., Associate Professor, Departments of Surgery and of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California


• Too many epigenomic profiles are from mixed tissues
• What is needed to achieve detailed epigenetic profiles of different cell types within organs? Expertise in purifying cell types from organs? Profiling high-quality epigenomics with limited cell numbers?
• What low cell input techniques (iCHIP, ATACseq and low-input bisulfide sequencing) exist to overcome this?

Chromatin Regulator Mutations in Human Cancers

Cigall Kadoch, Ph.D., Assistant Professor, Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School


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Wednesday, February 18

7:00 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

8:00 Plenary Session PANEL

9:45 Refreshment Break and Poster Competition Winner Announced in the Exhibit Hall


DNA METHYLATION BIOMARKERS IN CANCER

10:35 Chairperson’s Remarks

Michelle M. Hanna, Ph.D., CEO & Scientific Director, RiboMed

10:45 DNA Methylation as Cancer Biomarkers in Clinical Development

David Shames, Ph.D., Senior Scientist, Genentech

11:15 Development of DNA Methylation Markers for Early Lung Cancer Detection

Ite A. Laird-Offringa, Ph.D., Associate Professor, Departments of Surgery and of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California

Epigenetic modifications, i.e. modifications layered on top of the genome, play a critical role in determining cell phenotype, including the phenotypes of diseased cells. DNA methylation is a key epigenetic modification that can be measured from purified DNA, providing an advantage over protein-based epigenetic marks. We are developing DNA methylation as a lung cancer marker. Cancer DNA is shed into the blood and can in principle be used to non-invasively detect a cancer signature in bodily fluids. We have mined our own and publicly available data to identify DNA methylation markers present with high penetrance in lung cancer tumors. Our six-marker panel is detected as two panels of three, in a multiplexed digital readout. We are optimizing detection of this panel in the blood of early stage lung cancer patients, focusing on increasing sensitivity and determining the possible sources of background signal in subjects with benign lesions or control subjects with no detectable cancer. Given that low-dose spiral computed tomography, the state-of-the-art and only tool currently available for lung cancer early detection, has a false positive rate of 96%, there is a great need for additional complementary biomarkers.

11:45 Simultaneous Glioma Grading and Drug Response Testing with DNA Methylation Profiling

Michelle M. Hanna, Ph.D., CEO & Scientific Director, RiboMed Biotechnologies, Inc.

Human gliomas are classified by WHO grade using histopathology based examination of stained slides. This grade is used to establish prognosis and to determine a treatment plan. Unfortunately, there are significant inter-observer and intra-observer variability in the grading of Gliomas, and, many patients do not respond to the chemotherapy they receive. We have developed a sensitive, quantitative, bisulfite-free, fluorescent Glioma stratification test based on DNA methylation profiling of 6 genes using FFPE Glioma samples. The methylation level of three genes (SOWAHA, MAL, HFE) objectively separate tumors into high grade vs low grade Gliomas (HGG vs LGG). The methylation status of a fourth gene, MGMT, predicts response to temozolomide, the primary drug given for brain tumors. Methylation of the ASS1 gene predicts response to another class of brain tumor drugs which function by depleting arginine levels in the patient’s blood. The status of all 6 genes can be determined with a single FFPE sample with a tumor cross section as small as 2 µm, providing physicians with a new tool for the diagnosis and treatment of brain cancer.

12:15 pm Session Break

12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:00 Refreshment Break in the Exhibit Hall and Last Chance for Poster Viewing


IMPROVING DISEASE-RELEVANT ANALYSIS OF EPIGENOMEs

1:40 Chairperson’s Remarks

Yijun Ruan, Ph.D., Professor and Director, Genome Sciences, Jackson Laboratory Genomic Medicine

1:50 New Avenues for Studying Gene Regulation in Clinical Cancer Research using DNA Methylation Sequencing

Benjamin P. Berman, Ph.D., Assistant Professor, Bioinformatics, Preventive Medicine; Member, USC Epigenome Center, University of Southern California

Altered control of transcriptional regulation via mutations to transcription factors and chromatin modifiers is a hallmark of cancer. DNA methylation has long been the chromatin biomarker of choice in disease studies because of its stability under clinical collection conditions. By sequencing complete tumor methylomes, we have found that DNA methylation patterns can reveal a number of important gene regulatory processes, such as nucleosome organization, transcription factor binding, and 3D nuclear topological domains. We are also exploiting the unique properties of bisulfite sequencing to develop a “single molecule epistate” method to decompose complex tissue mixtures into their constituent cell types. These approaches open new avenues for studying chromatin changes and gene regulation in primary patient samples.

2:20 Interactive and Exploratory Visualization of Epigenome-Wide Data

Héctor Corrada Bravo, Ph.D., Assistant Professor, Computer Science, UM Institute for Advanced Computer Studies & Center for Bioinformatics and Computational Biology, University of Maryland

Data visualization is an integral aspect of the analysis of epigenomic experimental results. Commonly, the data visualized in these tools is the output of analyses performed in computing environments like _Bioconductor_. These two essential aspects of data analysis, algorithmic/statistical analysis and visualization, are usually distinct and disjoint but are most effective when used iteratively. We will introduce epigenomics data visualization tools that provide tight-knit integration with computational and statistical modeling and data analysis: _Epiviz_, a web-based genome browser application, and the _Epivizr_ Bioconductor package that provides interactive integration with _R/Bioconductor_ sessions. This combination of technologies permits interactive visualization within a state-of-the-art functional genomics analysis platform. The web-based design of our tools facilitates the reproducible dissemination of interactive data analyses in a user-friendly platform. We will illustrate these tools via analyses of the colon cancer epigenome, in particular, the relationship between clonal and population heterogeneity as inferred from DNA methylation sequencing data.

2:50 3D Genome Conformation and Gene Transcription Regulation in Human Diseases

Yijun Ruan, Ph.D., Professor and Director, Genome Sciences, Jackson Laboratory Genomic Medicine

The linear form of DNA sequences in a human genome is about 2 meters long, which has to be folded in micrometer-sized nuclear space for proper functions. Although most of our current understandings of the human genome functions are based on linear explanations, it has been speculated that the 3-Dimension (3D) conformation and high-order organization of the genome must play important roles in shaping the mechanisms of nuclear processes such as transcription regulation and DNA replication. Recent advances in DNA sequencing has allowed the development of high-throughput technologies for mapping genome-wide chromatin interactions, and sophisticated computational programs are able to reconstitute the 3D structure of the genome. This talk will highlight the most recent advances in studying genome organization and discuss novel insights of gene transcription regulation in human diseases.

3:20 Sponsored Presentations (Opportunities Available)

3:50 Refreshment Break


MECHANISMS UNDERPINNING DISEASE:
DNA METHYLATION

4:00 Chairperson’s Remarks

Lucy A. Godley, M.D., Ph.D., Associate Professor, Medicine, Hematology/Oncology, Cancer Research Center, The University of Chicago

4:10 Control of Cell Differentiation and Phenotype by 5-Hydroxymethylcytosine

Lucy A. Godley, M.D., Ph.D., Associate Professor, Medicine,Hematology/Oncology, Cancer Research Center, The University of Chicago

We now appreciate that there are multiple covalently-modified cytosine species within mammalian DNA- 5-methylcytosine (5-mC), 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC). My laboratory is particularly focused on deciphering the functions of 5-hmC, especially during cellular differentiation and in response to the microenvironment. We find that 5-hmC levels change dramatically as the hematopoietic stem cell differentiates into erythrocytes, with gains of 5-hmC occurring near the binding sites for erythroid transcription factors in concert with activating histone marks, suggesting that 5-hmC contributes to chromatin accessibility. In addition, we find that 5-hmC is an essential component of the transcriptional induction of hypoxia-responding genes, where the base acts to demethylate the HIF binding site, allowing the transcription factor to activate transcription from its target genes. Thus, we find that 5-hmC is a key element of transcriptional regulation.

4:40 DNA Methylation in Cancer and Other Human Diseases

Taiping Chen, Ph.D., Associate Professor, Department of Molecular Carcinogenesis, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center

DNA methylation is a key epigenetic modification involved in a variety of biological processes, such as gene regulation, genomic imprinting, X chromosome inactivation, and maintenance of genome integrity. DNA methylation is mediated by three DNA methyltransferases (DNMTs), DNMT1, which primarily maintains existing DNA methylation status during DNA replication, and DNMT3A and DNMT3B, which function as de novo methyltransferases that establish DNA methylation patterns and instigate methylation changes. Aberrant DNA methylation patterns are associated with human diseases, including cancer. The importance of DNA methylation is further highlighted by the identification of mutations in DNA methylation machinery, including DNMTs, TETs and MeCP2, in various human disorders. For example, DNMT3A is frequently mutated in hematological malignancies and developmental growth disorders and DNMT3B mutations cause the ICF syndrome, a rare autosomal recessive disorder characterized by Immunodeficiency, Centromeric instability, and Facial anomalies. In this presentation, I will discuss recent progress in understanding the mechanisms by which DNMT mutations and aberrant DNA methylation contribute to disease phenotypes.

5:10 Heritability of Epimutations in Cancer-Prone Families

Megan Hitchins, Ph.D., Associate Professor, Department of Medicine, Division of Oncology, Stanford School of Medicine

Epimutation, defined as an epigenetic error that results in altered gene expression within normal cells, has been identified as an alternative cause to genetic mutation for high-risk cancer syndromes. Some epimutations are associated with underlying cis-acting genetic defects and thus conform to Mendelian inheritance patterns, whilst others appear to have no genetic basis, and are either erased between generations, or demonstrate non-Mendelian vertical transmission. The role and inheritance patterns of MLH1 epimutation in Lynch syndrome will be the focus of this presentation.

5:40 Close of Conference Program



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