A busy summer schedule prevented us from checking out the TCEC in person, but Georgia Institute of Technology & Emory University’s Jessilyn Dunn made the journey to the City by the Bay for the first of what promises to be a great conference series. Check out Jessilyn’s conference report below:
Nestled in the heart of Japantown amidst sushi houses and anime shops, the inaugural Clinical Epigenome Conference (TCEC) was held alongside the sister Clinical Genome Conference (TCGC) at the Hotel Kabuki in San Francisco. While marriage abounded at City Hall after the historic supreme court overturn of DOMA, the tight-knit community of ~40 epigeneticists at TCEC joined with fellow geneticists at TCGC to tackle methods of dealing with unwieldy datasets being pumped out at a lightning pace.
Joint presentations highlighted the difficulty of data storage, accessibility, and analysis. A number of companies were represented, including genome browsing and parsing softwares, open source web-based bioinformatics platforms such as Galaxy and the Human Epigenome Atlas, and applications for bench-to-bedside genomics-based personalized medicine.
The first day of talks at TCEC focused on the role of DNA modifications in cancer. The grey area of separation between the genome and epigenome, and the tight interplay between the two, was exemplified by mutations in genomic regions encoding epigenetic modifiers that cause altered chromatin accessibility and transcriptional changes.
Spontaneous and Therapy-Induced Evolution of Tumor Genomes and Epigenomes
Joseph Costello, University of California, San Francisco
Dr. Costello gave the keynote presentation on low grade glioma, a slow growing brain tumor that is quite survivable for some patients but takes a deadly turn for others. Single nucleotide polymorphisms in IDH1 and ATRX are high-risk mutations in primary tumors that likely have downstream epigenetic effects causing further malignancy.
Costello presented astonishing data on the rate of tumor cell mutation with or without Temozolomide (TMZ) treatment, an alkylating chemotherapy drug, given a patient’s particular epigenetic landscape at mismatch and DNA damage repair genes such as MGMT. Costello showed evidence of a likely role of TMZ induction of hypermutation when these genes are epigenetically altered in the tumor, indicating that treatments should be tailored not only to genetic mutations, but also to epigenetic alterations in the tumor versus normal tissue. This study should lead to a careful examination of current epigenetics-based chemotherapy strategies.
The Epigenetic Landscape during Normal and Malignant Hematopoiesis
Lucy A. Godley, The University of Chicago
Dr. Godley’s work was stimulated by the difficulty of predicting how Acute Myeloid Leukemia patients would respond to hypomethylating agents, and whether baseline epigenetics could lend important information for treatment strategies. Godley studied covalent cytosine modifications using high-density methyaltion arrays and 5-hydroxymethylcytosine (5hmC) affinity sequencing in normal and leukemic hematopoietic stem cell development. Her group also examined baseline cytosine modifications between African and European populations, showing ~36,000 distinct CpG modifications between the two groups.
Dr. Godley emphasized the importance of 5hmC, the late-blooming cousin of 5-methylcytosine (5mC) that has eluded experimenters until recently. While 5hmC and 5mC have distinct functionality (5hmC is thought to play a role as an intermediate between 5mC and unmodified C, but also may have its own transcriptional regulatory role), current bisulfite-based “methylation” assays cannot distinguish between 5mC and 5hmC. Accordingly, while traditional bisulfite sequencing methods may show no change in “methylated” DNA, there may be dynamic changes between 5hmC and 5mC that fly under the radar. Thus, bisulfite sequencing product cytosines should more accurately be referred to as modified, rather than methylated, cytosines.
Single-Base Resolution Mapping of DNA Epigenetic Marks: OxBS-Seq and RedBS-Seq
Michael Booth, University of Cambridge
Conveniently, Michael Booth of the Balasubramanian lab at the University of Cambridge has developed a technique to map the location of 5hmC marks via oxidative bisulfite sequencing (OxBS-Seq). OxBS-Seq is similar in theory to normal bisulfite sequencing, except the resultant cytosines represent only 5mC, rather than both 5hmC and 5mC as in traditional bisulfite sequencing. Simple subtraction of OxBS-Seq from BS-seq results shows where 5hmC are situated.
The initial OxBS-Seq paper was covered by EpiGenie and the newly commercialized kit can be purchased from Cambridge Epigenetix. Booth has also developed a method to distinguish 5-formylcytosine from 5mC and 5hmC via reduced bisulfite sequencing, or RedBS-Seq.
The DNA Methylation “Cityscape” of Lethal Metastatic Prostate Cancer
Srinivasan (Vasan) Yegnasubramanian, Johns Hopkins University School of Medicine
Dr. Yegnasubramanian presented his novel visualization technique of “methylation cityscapes” to decode complex genome-scale DNA methylation alterations, an idea conceived from his studies of prostate cancer patients to discover potential “driver” DNA methylation changes that lead to downstream metastasis.
His group discovered that metastatic tumors have unique DNA methylation signatures for an individual patient that link together with copy number variations, but that were distinct across patient populations. This suggests a clonal origin and downstream maintenance of methylation patterns in disseminated metastases within a patient. Interestingly, intergenic regions, 3’UTRs, and intron/exon boundaries were implicated as potentially functional differentially methylated culprits as frequently as the better-understood promoter region of genes.
DNA Methylation Detection using Nanopores
George Vasmatzis, Mayo Clinic and Foundation
With our current cumbersome experimental techniques for methylation analysis, it was a breath of fresh air to hear about a quick and simple method under development by Dr. Vasmatzis. This biosensor approach is similar to nanopore-based DNA sequencing technologies that use the change in electrical charge as the DNA passes through the nanopore to determine the identity of each base pair.
The proposed DNA methylation detection method uses methyl-binding domain proteins that bind methylated cytosines with a high affinity, and can then be detected upon passage through the nanopore. Although this technology is in a very early stage and will require more thorough development, the basic technology was shown to work and is very exciting for future epigenetics research.
TCEC presented a very interesting overview of the state of applied epigenetics research. While the utility of epigenetic-based cancer therapeutics was highlighted, the meeting did not cover advancements outside the realm of cancer biology, including neurological, cardiovascular, and other diseases of aging that are now known to have an important epigenetic basis. Additionally, the focus on cytosine modifications left histones and microRNAs feeling a bit neglected. Overall, the data presented may cause clinicians to rethink current chemotherapeutic strategies while baseline and disease epigenetic landscapes continue to be reshaped.
**EpiGenie would like to thank Jessilyn Dunn, who is a Graduate Research Fellow in the Jo lab at the Georgia Institute of Technology & Emory University for contributing this excellent conference coverage!**