The 5th Wellcome Trust Epigenomics of Common Diseases conference was held in Cambridge on November 6-9th and brought together leading scientists from the fields of epigenomics, genetics and bioinformatics to discuss the latest developments in this fast-moving area. Epigenetic variation plays an important role in disease processes and provides a promising focus for disease prediction, prevention and treatment. Below you find some summaries to let you enjoy the (r)evolutions in the field.
Exploring the relationship between chromosome structure and function in development and disease using X-chromosome inactivation as a paradigm
Edith Heard (Institut Curie, France)
Edith Heard gives insights into the regulatory landscape of the Xic, including partitioning into topological associating domains (TADs) and its genetic dissection. In addition, Edith Heard offers new insights in X-chromosome inactivation (XCI). She opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological level in cancer. Genome-wide profiling of chromatin and transcription revealed modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. In the future, the application of single-cell technologies and live cell imaging will be key to our understanding of the temporal dynamics of XCI and their functional relationships.
X-chromosome inactivation: new insights into cis and trans regulation.
The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.
Chronic colitis of male mice contributes to epigenetic changes and an increased susceptibility to colitis in offspring mice
Priyadarshini Kachroo (Christian Alberts University, Germany)
Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder that arises as a combination of both environmental and genetic risk factors in immunocompromised individuals. Priyadarshini Kachroo from the Christian Alberts University in Germany shows us how an environmentally induced inflammation contributes to the trans-generational inheritance of IBD. Chronic colitis was induced in male wild-type C57BL/6 mice by adding dextran sulphate sodium (DSS) to their drinking water. Offspring of diseased males had lower body weight and were more prone to develop colitis than offspring of healthy males. After RRBS and RNA-Seq, they identified 823 significantly differentially methylated sites in sperm cells of F0 males after DSS treatment, some of which (n=66) were also observed in offspring. Intriguingly, these paternally acquired traits led to a differential methylation and expression profile in the intestinal epithelium of F1 generation.
Epigenetics of stem cell activation and aging
Thomas Rando (Stanford University, USA)
Thomas Rando from Stanford University, USA, poses the question whether aging is reversible? For most tissues, stem cell numbers decline negligibly with age, but there is nevertheless an age-dependent decline in stem cell functionality. Thomas Rando shows compelling data from studies of heterochronic parabiotic pairings of mice, and it is clear that the aged phenotype can be modified when aged cells are exposed to a youthful systemic milieu. In addition, Thomas Rando investigated epigenetic profiles of young, old, and “rejuvenated” old stem cells to attempt to define youthfulness and aging in epigenetic terms. He found changes in patterns of chromatin modification that occur during the aging of quiescent stem cells. In particular, there is a marked increase in the enrichment of the repressive mark, H3K27me3, at transcription sites along the genome, a change that was also observed as quiescent stem cells activate and enter the cell cycle. This study will provide a framework to understand the fundamental molecular mechanisms of aging and the mechanisms by which environmental influences can reverse the mechanisms of aging.
Epigenetics of lactose intolerance and lactase persistence
Viviane Labrie (University of Toronto, Canada)
Why is lactase (LCT) very active in the intestine of newborns, but later declines dramatically in most (+/- 65%), but not all, adults worldwide? To address this question, Viviane Labrie investigated epigenetic regulation of LCT in the human intestine using chromosome-wide DNA modification profiling and targeted bisulfite sequencing. She identified 7 sites exhibiting major DNA modification differences that direct LCT mRNA levels in lactose intolerant and lactase persistent adults. These sites account for the age-dependent, cell-type specific and interindividual differences in LCT mRNA. The discovered regions contained chromatin signatures of enhancers. Next, they investigated the causal role of the enhancers by deleting them via CRISPR-Cas9 mutagenesis. This resulted in significant loss in lactase expression in mice and a human intestinal cell line. Integration of genetic analyses with this epigenetic investigations revealed that different DNA haplotypes show differential epigenetic aging patterns. In conclusion, lactose intolerance is produced by the synergistic effects of the inherited haplotype and acquired age-dependent epigenetic modifications.
The role of epigenetic variation in metabolic disease
Charlotte Ling (Lund University, Sweden)
Charlotte Ling from the Lund University in Sweden identified altered DNA methylation p atterns in pancreatic islets, the liver, skeletal muscle and adipose tissue from patients with type 2 diabetes compared with non-diabetic controls. They showed also that environmental factors, including exercise and diet, affect the DNA methylation pattern in human skeletal muscle and adipose tissue. Moreover they demonstrated that polymorphisms associated with type 2 diabetes directly modify the epigenetic pattern in human tissues. This study proposes that combinations of genetic, epigenetic and non-genetic factors contribute to metabolic disease and type 2 diabetes.
Methylation quantitative trait loci (mQTL) in the developing human brain and their enrichment in genomic regions associated with schizophrenia
Jonathan Mill (University of Exeter, UK)
Jonathan Mill from the University of Exeter (UK) characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n=166) of human fetal brain samples, identifying > 16,000 mQTLs. They showed that most fetal brain mQTLs are developmentally stable, although a subset was fetal-specific. Fetal brain mQTLs are enriched amongst risk loci identified in a recent large-scale GWAS of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Overall, Jonathan Mill showed how mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.
Methylomic trajectories across human fetal brain development.
Epigenetic repression of transposons by an RNA-based innate immune system
Greg Hannon (CRUK Cambridge Institute, UK)
The Piwi-interacting RNA (piRNA) pathway is a small RNA-based innate immune system that defends germ cell genomes against transposons. Greg Hannon sought to understand the connections between the piRNA pathway and the general repressive machinery that it must recruit in flies and mammals to create epigenetically heritable marks. Recently, they have shown that CG9754 is a component of Piwi complexes that functions downstream of Piwi and its binding partner, Asterix, in transcriptional silencing. Greg Hannon named CG9754 Panoramix, and proposed that this protein could act as an adaptor, scaffolding interactions between the piRNA pathway and the general silencing machinery that it recruits to enforce transcriptional repression.
Panoramix enforces piRNA-dependent cotranscriptional silencing.
Combinatorial epigenetic approaches for genome engineering: from zinc-fingers to novel epigenetic tools
Pilar Blancafort (The University of Western Australia)
Pilar Blancafort developed novel precision molecular medicine strategies to selectively revert or reprogram the aberrant gene expression and epigenetic state of prospective cancer drivers in breast and ovarian tumors. Therefore they engineered a novel generation of sequence-specific DNA-binding molecules with the capacity to recognize specific sequences in cancer genome. These DNA-binding domains (DBDs) are designed to bind promoters, enhancers and other regulatory regions controlling the expression of the targeted loci. They are linked to effector domains able to modify and edit chromatin, for example by inducing or removing DNA methylation, histone post-transcriptional modifications, or by promoting irreversible DNA damage in specific oncogenic loci. Interestingly, a combinatorial approach utilizing different platforms or molecular backbones (Zinc Fingers, TALEs and CRISPR-based genome ediging tools) linked to different epigenetic regulators, are highly synergistic in regulating endogenous targets. This research generates multimodal, combinatorial state of the art genome engineering tools for reprograming and normalization of the epigenome in cancer and other systems.
Epigenome engineering in cancer: fairytale or a realistic path to the clinic?
Epigenome editing with CRISPR/Cas9 technologies for programming cell phenotype and functional genomics
Charles Gersbach (Duke University, USA)
Charles Gersbach engineered CRISPR/Cas9-based tools to regulate the expression of endogenous genes and applied these tools to control genes relevant to medicine, science and biotechnology. By varying the effector domains incorporated into these synthetic transcription factors they can generally activate or repress gene expression, or manipulate the status of a particular epigenetic mark at a specific genomic target site. He recently applied these technologies to control the decisions of stem cells to become specific cell fates and reprogram cell types into other lineages that could be used for drug screening and disease modelling. Incorporating methods to dynamically control the activity of these proteins, such as optogenic control of the proteins with light, has allowed them to pattern gene expression both temporally and spatially.
Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements.
Collectively, these studies demonstrate the potential of modern genome engineering technologies to program cell behaviour by manipulating gene networks and epigenomic states with precision that was not previously possible.
** We’d like to extend big thanks to Anne Rochtus, at the University of Leuven, who was kind enough to bring you this great coverage