Anne Rochtus from University Hospital Leuven supplied us with a blow-by-blow account of the recent Epigenomics of Common Diseases meeting held on November 7-11th, 2013. Read on to check out her report:
The 3rd Wellcome Trust Epigenomics of Common Diseases conference in Cambridge brought leading scientists from the epigenomic, genetic and bioinformatic field together. Hereafter you can have a glance at what happened during these four days full of interesting lectures and discussions bridging genetic and epigenomic changes in the development of diseases!
CRISPR/Cas9: On the Cutting Edge
George Church, Harvard Medical School
Dr. Church opened the conference by giving an overview of new technologies for Sequencing. Assessing a variety of genomic variants, they enable us to move from correlation to causality studies. Moreover Dr. Church gave an overview of new CRISPR technologies for (epi)genomic engineering. For example fully orthogonal Cas9 proteins from Streptococcus pyogenes are able to mediate simultaneous and independently targeted gene regulation and editing in bacteria and in human cells. These orthogonal RNA-guided proteins are a novel method to target any place of the epigenome, without changing the epigenome … Further information is available in Esvelt et al, Nature Methods 2013.
Epigenetics in Epidemiology
Daniele Fallin, Johns Hopkins University
Dr. Fallin continued with a nice overview of the role of epigenetics in genetic and environmental epidemiology. Epigenetics may represent a mechanistic link between environmental exposures and many common diseases. However, these marks also appear to be at least partially controlled by genetic sequence, and we are still learning the relative role of genes versus environment in epigenetic variability within and across people.
Genetic causes or modifiers interact in two ways with the epigenome: epigenetics is a mediator of genetic effects but the penetrance of a genotype may be dependent on the epigenotype (Ex. imprinting diseases) … on the other hand diseases have epigenetic consequences (reverse causality) and the epigenome has a certain environmental susceptibility …All of these findings have implications for how epigenetic measures are used in epidemiologic research.
Regulatory Relationships Between CpG islands and Chromatin Strucutre
Rob Klose, University of Oxford
Dr. Klose explained how CpG island (CGI) elements may contribute to the function of gene regulatory elements through the utilization of chromatin and epigenetic processes. CGI have an elevated level of non-methylated CpG dinucleotides and are often associated with genes, 70-75% of our genes have a CGI next to the promoter site. Their association with promoter and regulatory elements suggest they likely contribute to gene regulatory processes, but the presence of a CpG island alone does not define transcriptional output. What do CGI and CGI chromatin architecture contribute to gene regulation?
Recently it has become clear that CGIs are specifically recognized by a class of histone modifying enzymes that interpret the non-methylated CpG signal and translate this into a unique chromatin environment at CGI elements. Non-methylated CpGs act as a signal for ZF-CxxC protein binding at CGI. Rather than defining the active or repressed transcriptional state, CpG island elements utilize chromatin-based processes to create environments that contribute to the transcriptional potential of the associated gene.
DNA Methylation in Reprogrammed Stem Cells
Stefan Stricker, University College of London
Dr. Stricker applied induced pluripotent stem cell (iPSC) reprogramming techniques to invoke widespread resetting of glioblastoma-derived neural stem (GNS) cells. Glioblastoma iPS cells were subsequently re-differentiated to the neural lineage to assess the impact of cancer-specific epigenetic abnormalities on tumorigenicity. GiPSCs and their differentiating derivatives display widespread resetting of common GBM-associated changes, such as DNA hypermethylation of promoter regions of the cell motility regulator TES, the tumour suppressor CDKN1C and many polycomb repressive complex 2 target genes. Surprisingly, GiPSCs-derived neural progenitors remained highly malignant upon xenotransplantation. Only when GiPSCs-derive neural progenitors were directed to non-neural cell types sustained expression of reactivated tumours suppressors and reduced infiltrative behaviour was observed. To conclude widespread resetting of GBM-associated epigenetic abnormalities is not sufficient to override the cancer genome!
oxBS-seq for 5-hmC Quantitation
Shankar Balasubramanian, University of Cambridge
Dr. Balasubramanian made his audience feel a bit uncomfortable by starting with “Why you don’t have to use bisulfite treatment …”. Chemical modifications fundamentally alter how biology sees DNA structure and the genome. Bisulfite treatment chemically alters the Watson-Crick bases and often you don’t know anymore whether you’re looking at 5-methylcytosine (5mC) or 5-hydroxymethylcytosine (5hmC) …The Balasubramanian laboratory developed oxidative bisulfite sequencing (oxBS-seq), which can quantitatively locate 5mC and 5hmC marks at single-base resolution in genomic DNA. In oxBS-seq, specific oxidation of 5hmC to 5-formylcytosine (5fC) and conversion of the newly formed 5fC to uracil means that 5hmC can be discriminated from 5mC. And of course you can go on using bisulfite treatment to discover our epigenetic code …
Quantitative Epigenomics and Computational Analysis
James Zou, Microsoft Research in Cambridge (USA)
Dr. Zou proposes a novel method, EWASher (principal components adjusted linear mixed model), that automatically corrects for cell type heterogeneity, without cell-type compositions knowledge. They validated their method on a bronze standard methylation data set with cell-type composition information, and demonstrated that EWASher performs as well as the state-of-art method. They also applied the EWASher to breast and colon cancer methylation data from the Cancer Genome Atlas, where no cell-type composition data available, and found disease-relevant associations not obtainable by standard analysis. To conclude the EWASher is a novel method that automatically accounts for cell composition without references, that works fast (1-4 minutes) for 27K, 450K and sequencing data.
Imprinted gene silencing in mammals
Denise Barlow, Univeristy of Vienna
Dr. Barlow gave an overview of imprinted gene silencing by macro lncRNA transcriptional interference. Imprinted expression is tissue specific and developmentally regulated. We still do not fully understand imprinted gene expression.
Two important questions are whether all lncRNAs are functional and how they could exert a function. Several lncRNAs have been shown to function through their product, but the process of lncRNA transcription, independent of the lncRNA product, has an important role in regulation protein-coding-gene activity in cis. The imprinted Airn macro long non-coding RNA is an established example of a cis-silencing lncRNA. Airn expression is necessary to initiate paternal-specific silencing of the Igf2r gene, which is followed by gain of a somatic DNA methylation imprint on the silent Igf2r promoter.
The Barlow laboratory recently showed that Igf2r silencing only requires transcription of unspliced Airn across the Igf2r promoter and is not dependent on the Airn lncRNA product or on repressive chromatin modifications. Imprinted lncRNAs that silence genes in cis, possess atypical features – such as inefficient splicing, extreme length, high repeat content, lack of transcript conservation and short half-life – that together indicate their transcription is more important than their RNA product. Mainly there are two types of imprinted lncRNAs: inefficiently spliced ‘macro’ lncRNAs and efficiently spliced ‘mRNA like’ lncRNAs. However, it is not yet known how many of the growing number of mammalian lncRNAs share hallmarks features of macro lncRNAs.
This conference emphasizes the importance of understanding the role of the epigenome in disease regulation. Like George Church commented, “Genes interact with the environment to form traits …”. Our task is to unravel this underlying hidden code, taking into account all the different ways of interaction. Novel technology and sharing knowledge help us to go on …
Thanks a lot to all the people from the Wellcome Trust Centre, that made it possible to enjoy this magnificent conference.
**EpiGenie issues a hearty thanks to Anne Rochtus, who is a PhD student in the Center for Molecular and Vascular Biology at University Hospital Leuven, for providing this conference coverage.