Thanks to Roxane Verdikt for this informative coverage of the Blueprint/IHEC meeting.
The Blueprint/IHEC (International Human Epigenetic Consortium) Science Days meeting was held in Brussels on September 7-9 and saw the celebration of the end of the 5-year Blueprint adventure.
Blueprint was one of the first high impact research initiatives funded by the EU, as part of the 7th Framework Programme, and gathered more than 41 leading European universities, research institutes and industry entrepreneurs, with the main aim of unravelling the epigenetic landscape of blood-based diseases. It was therefore no surprise that the different talks and posters presented in Brussels proved to be both of high quality and very exciting.
The meeting revolved around seven sessions, covering the different work packages of the Blueprint consortium, including research projects in epigenetic variation and their use for the improvement of human diseases diagnosis (leukemia, gastric cancers, diabetes,…), the establishment of novel technologies for high-throughput epigenome mapping, the development of new compounds interfering with regulators of epigenetics profiles (with the big success of the JQ1 drug), but also, more computing approaches both for epigenomes data coordination and analysis (with the aim of providing 100 human reference epigenomes for researchers).
Altogether, the vast community of Blueprint enabled to bring back together a wider group of focused interests, which prompted many collaborations and gave rise to many thrilling publications.
You’ll find here a selection of the meeting highlights, however, a broader overview of the research conducted in the Blueprint consortium can be obtained on their website (http://www.blueprint-epigenome.eu).
The nanoscale structure of chromatin fibers in somatic and stem cells
Maria Pia Cosma | Centre for Genomic Regulation, Barcelona, Spain
Maria Pia Cosma’s group developed tools to visualize how chromatin can be remodeled. Light diffraction limits the resolution of classical microscopy, however, using stochastic optical reconstruction and photo-activated localization microscopies (STORM-PALM), a higher resolution of 20nm can be obtained, enabling the study of chromatin fibers.
Coupling photo-switchable fluorophores to antibodies directed against histones (or directly fluorophores-fused histones), they resolved histone organization in living cells. This approach also provides quantitative information regarding histone localization within sub-nuclear entities, for instance, during the development of mouse embryonic stem cells to neuron progenitors.
Indeed, dense “nucleosomes clutches” associated with heterochromatin are more represented in differentiated cells, while, more pluripotent cells have a lower nucleosome per clutch ratio. In the future, studies on chromatin remodeling and nucleosome occupancy in live-imaging could be envisioned, even though, these experiments will probably be quite tricky.
Peter Jones | Van Andel Institute, Grand Rapids, USA
Peter Jones’ lab is focused on the misregulation of epigenetic mechanisms in cancer. Recently, they further investigated the mechanisms of action by which DNA-demethylating agents, such as the 5 aza-2’-deoxycytidine nucleotide analog (5-AZA-CdR), could target colorectal cancer-initiating cells.
Indeed, while this DNA-demethylating agent is used for the treatment of some cancers, including acute myeloid leukemia, its anti-tumor mechanism was still unknown. Using cDNA microarrays, Jones’ team showed that many genes expressed in late response to 5-AZA-CdR were linked to antiviral response, that was due to the induction of endogenous retroviruses.
Therefore, they concluded that the 5-AZA-dCR induction of “viral mimicry” in cancerous cells was its anti-tumor mechanism. The pathway of endogenous retrovirus clearance by the immune system thus represent druggable targets, in the context of the development of new therapeutic approaches for cancer therapies.
Single cell genomic analysis of the immune system
Ido Amit | Weizmann Institute, Rehovot, Israel
Ido Amit’s group focuses on decomposing the complexity of immune cells differentiation during immune response in terms of gene regulatory networks. To do so, they have focused on single-cell approaches such as MARS-seq (MAssive parallel single-cell RNA-Seq) that provides an immune cellular atlas of transcription profiles.
Using MARS-seq, Amit’s team showed that myeloid progenitors, previously thought as a homogenous population giving rise to erythrocytes, monocytes/macrophages and megakaryocytes, can be subdivided into 19 functionally diversified subpopulations.
These subpopulations present transcriptional specificities towards the different fully differentiated cells they give rise to, but also, chromatin profiling show transcriptional priming with the in vivo development commitment. From these descriptive studies, Amit’s team has moved to more functional studies, including the combination of MARS-seq with CRISPR pool technology, in which single-cell readout of transcriptomes induced by the CRISPR library knock-out serve to define the functions of heterogeneous immune populations. These studies participate in reshaping the hematopoietic differentiation tree as we know it, and this advanced immunology understanding may help to better define immune therapy.
Vitamin C-induced methylome in leukemic models
Martin Hirst | British Columbia Cancer Agency, Vancouver, Canada
Martin Hirst’s team focuses on the implication of environmental stimuli, including nutrient levels and toxin exposure, on the epigenetic profile in the initiation and progression to disease. Particularly, they studied the role of vitamin C in embryonic stem cells and showed that it provokes DNA demethylation through a transient increase in DNA hydroxymethylation by Tet2 activation.
Since Tet2 is often reported mutated in cancer cells, they next investigated how vitamin C can reverse epigenetic alterations in leukemic cells that harbor Tet2 mutations.
They showed that demethylation was localized in enhancer regions that bind PU.1 transcription factor and developed a molecular model by which vitamin C works on Tet2 recruitment to enhancers. Altogether, their studies point towards the use of vitamin C as a new class of epigenetic therapeutics.