15 projects, 1 topic : epigenetics
ESR 1 project : Dissection of coordinated stress responses by novel promoter elements with enhancer activity (WP1)
We recently demonstrated that a subset of gene promoters, termed Epromoters, works “also” as bona fide enhancers and regulate distal gene expression. Subsequently, we found that Epromoters play a key role in the coordination of rapid gene induction in the stress response, in particular during inflammation. The ESR will study the functional role of Epromoters in different stress and inflammatory conditions, determine their impact in genome topology, and establish in vivo models to assess Epromoter variation in inflammatory diseases. This systematic approach will unravel the basic molecular mechanisms of this novel type of regulatory elements and shed the basis of their potential involvement in diseases.
Supervisor : SALVATORE SPICUGLIA
Coordinator & WP7 Leader
Institute Nationale pour la Santé et la Recherche Médicale (Inserm)
ESR 2 project : Modeling gene-environmental interactions implicated in the etiology of human neurocristopathies (WP3)
Using human neural crest cells and the TFAP2A locus as a medically relevant models, our work will evaluate whether genetic variants within enhancers might interact with teratogenic factors as part of the etiology of human congenital abnormalities. Thus, by considering enhancers as hubs of gene-environmental interactions, our results can illuminate a novel and broadly relevant etiological paradigm for human disease.
Supervisor : ALVARO RADA-IGLESIAS
Vice-coordinator & WP4 Leader
University of Cantabria
ESR 3 project : Genetic and epigenetic changes in hematopoietic stem cells (HSCs) during chronic inflammation (WP3)
This project will determine the molecular changes in enhancers and promoters that chronic inflammation induces in hematopoietic stem cells. Together, the results of this project will uncover the mechanisms regulating hematopoietic stem cell maintenance and fate in the context of chronic inflammation, and lay the path to identify new therapeutic strategies.
Supervisor : MERITXELL ALBERICH-JORDA
Institute of Molecular Genetics, Prague, Czech Republic
ESR 4 project : The impact of genetic variants on regulatory activities (WP1)
This project aims to explore the impact of regulatory genetic variation. In particular, the major aims are to establish accurate and interpretable machine learning approaches to learn how DNA sequence influences enhancer and promoter activities and to use derived models to interpret the determinants of regulatory function and the impact of regulatory genetic variation on their activities in health and disease. To this end, part of the project will focus on in vivo (CAGE, ATAC-seq, Hi-C) and in vitro (STARR-seq, SURE-seq) data generated in our lab and within the ENHPATHY network across a genotyped panel of lymphoblastoid cell lines, displaying large individual regulatory variation. Inferred models will further our understanding of the determinants of regulatory function and improve genetic variant interpretation, which will be useful for a large scientific and medical community, ultimately leading to insights into why and when regulatory genetic variation may cause phenotypical or pathological changes.
Supervisor : ROBIN ANDERSSON
University of Copenhagen
ESR 5 project : Understanding the impact of gene regulatory variation on disease using variable chromatin modules (VCMs) (WP2)
In this project, we will leverage the transformative power of VCMs to unravel how genetic and regulatory variation guides phenotypic diversity. We predict that the most likely causal variants are those that associate with VCM activity, gene expression, and organismal phenotypes (here, extent of differentiation). We will map VCMs both at the single cell and bulk level and exploit their coordinated molecular nature to uncover the flow of regulatory information, from causal nucleotides over gene(s) to phenotype. As such, we aim to provide unprecedented insights into the molecular mechanisms driving phenotypic variation.
Supervisor : BART DEPLANCKE
Swiss Federal Institute of Technology Lausanne
ESR 6 project : Computational approaches to discover noncoding mutations underlying human disease (WP3)
Human genetics is rapidly moving from the analysis of protein-coding sequences to whole genome sequences. Our ability to discern non-protein coding mutations that cause disease from a vast excess of non-functional mutations is still limited. This PhD project will focus on an ERC-funded large-scale enhancer mutation screen in patients with monogenic diabetes. It will develop computational approaches to inform on the pathogenicity and function of enhancer mutations, using data from ongoing experimental and patient screens.
Applicants with diverse educational backgrounds are welcome, but a computing background is important, including basic knowledge of a programming language (e.g Python, R). Expertise in statistical analysis is also highly relevant.
Supervisor : JORGE FERRER
ESR 7 project : Higher-order topological organization of super-enhancer hubs, Epromoters and TADs (WP2)
The project will characterize the functioning and impact of novel key topological factors on long-range regulatory and architectural chromatin interactions and hub formation, using state-of-the-art protein depletion, chromatin topology and microscopy technologies.
Supervisor : WOUTER DE LAAT
ESR 8 project : Enhancer networks in the control of lineage determination of human mesenchymal stem cells (hMSCs) (WP2)
The project will investigate functional and mechanistic aspects of the enhancer networks regulating adipocyte differentiation of human mesenchymal stem cells. In unpublished work from our laboratory, we have shown that differentiation is driven by highly connected connected enhancer communities that appear to be preprogrammed already at the stem cell state. In this project we will determine the mechanisms by which these enhancer communities are activated during differentiation.
Supervisor : SUSANNE MANDRUP
ESR 9 project : Analysis of the role of coregulators in the activity of cis-regulatory elements in response to inflammatory stimulation (WP1)
The project will address the mechanisms that control the function of cis-regulatory elements (enhancers and promoters) in basal conditions and in response to acute stimulation using the model of macrophages activated by inflammatory stimuli. In particular, the RNA Polymerase II recruited to both enhancers and promoters can generate a substantial amount of non-coding transcripts such as enhancer RNAs (eRNAs) and promoter-antisense RNAs. However, non-coding transcription efficiency at cis-regulatory elements is much lower compared to protein coding genes, suggesting the existence of mechanisms that attenuate RNA Pol II activity at these sites or conversely mechanisms that selectively enhance transcription within gene units. The work will entail the generation and computational analysis of multiple genomics data sets in normal cells or cells lacking a panel of novel candidate regulators.
Supervisor : GIOACCHINO NATOLI
ESR 10 project : The spatial organization of enhancers around promoter regions within chromatin contact domains for selected Human cell lines: structural regulatory landscape (WP2)
The objective of the research is to develop and test the concept of the structural landscape for regulatory elements around promoter regions for selected cell lines. We will propose novel biophysical method to construct probabilistic ensembles of three-dimensional conformations for chromatin contact domains (CCDs, sometimes described as TADs: topologically associating domains) at the whole genome scale. The computational method exploits results from two independent experimental sources: first the genomic-based interaction data from ChIA-PET together with epigenetic modifications and transcription factors binding sites occupancy (ChIP-seq), and secondly the mRNA expression profiles (RNA-seq) measured in the same cell lines. We will independently validate our findings and computational algorithms by extensive analysis of GWAS in relevant regulatory elements.
Supervisor : DARIUSZ PLEWCZYNSKI
University of Warsaw
ESR 11 project : Functional understanding of synergistic effects of enhancer elements at the onset of atherosclerosis (WP3)
The aim of the project is to establish a method that can resolve multiple promoter-anchored interactions at single cell resolution. The method will utilise droplet technology and chromatin immunoprecipitation to identify multiple promoters and enhancers contacts. Such data will help elucidate to which degree enhancers cooperate in regulating expression of their target genes, and contribute to our understanding of the role of enhancer redundancy in complex diseases context. We will apply the methodology to aortic endothelial and smooth muscle cells, liver cells and activated macrophages to study the extent of redundancy in regulatory networks concerning cardiovascular risk variants.
Supervisor : PELIN SAHLÉN
Royal Institute of Technology
ESR 12 project : Regulatory network guiding stem cell interactions within the hematopoietic niche using single cell genomics (WP1)
Integrating data from ou in vitro model of the bone marrow niche with publicly available data, this project will reveal regulatory interactions between enhancers and their target genes that are triggered by the interaction of HSCs with different types of niche cells. Regulatory interactions will be derived from co-variation of regulatory elements (ATAC-Seq) and gene expression (RNA-Seq) across individuals. Specifically, we will investigate the effect of mesenchymal stromal cells (MSCs) and MSC-derived cell types (adipocytes and osteoblasts) on the regulatory network of HSCs. These comparisons are particularly interesting since the bone marrow niche becomes more adipocyte-dense during aging. At the same HSCs show a differentiation bias of HSCs from lymphoid to myeloid lineages upon ageing, a phenomenon that has been linked to the weakening of the adaptive immune system with old age. Integrating the regulatory network with SNPs associated with common (immune-system related) diseases, as obtained from genome-wide association studies, will reveal how the age-dependent compositional change in the bone marrow niche might contribute to disease phenotypes.
Supervisor : JUDITH ZAUGG
European Molecular Biology Laboratory
ESR 13 project : Functional annotation 10 human genomes to aid the identification of disease-causing non-coding sequence variants (WP1)
We have previously shown how the SuRE assay can be used to test non-coding sequence variants for their effect on promoter and enhancer activity. In this project we will apply SuRE for around 10 individuals to functionally characterize their non-coding sequence variants. Combining these results with for example GWAS and eQTL data should enable us to identify putative causal variants.
Supervisor : JORIS VAN ARENSBERGEN
Legal Supervisor : SALVATORE SPICUGLIA
ESR 14 project : Microfluidic systems for encapsulation of molecular complexes (WP2)
The ESR project will develop into two main axes. We will support the other teams within ENHPATHY working with microfluidics (EPFL, KNAW and KTH) in order to provide them with our flow control system. In particular we will partner with Dr. Deplancke’s laboratory to support them in the development of their system. On the other hand, the ESR will lead, in collaboration with Dr. Sahlén’s group, the development of an automated microfluidic system for double encapsulation droplet production.
Supervisor : JULIA SEPULVEDA DIAZ
Legal Supervisor : PELIN SAHLÉN
ESR 15 project : Uncovering drug-adaptive epigenetic response in Acute Myeloid Leukemia (AML) (WP3)
This project will uncover drug-responsive regulatory elements and related molecular mechanisms that may have an impact on AML therapeutic outcomes and drug resistance. These results can pave the way to strategies with improved therapeutic efficacy by targeting of enhancers or their targets with inhibitors that can attenuate the adaptive transcription to genes related to drug resistance and proliferation.
Supervisor : MILEIDYS PEREZ
Legal Supervisor : SALVATORE SPICUGLIA
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