Project description
A method for studying the interplay of distant genomic regions
Gene expression is regulated through the complex interplay between cis-regulatory sequences and trans-acting elements located at distant sites. Dynamic changes in the activity of these elements underlie phenotypic variation and disease. To explain the molecular coordination between genomic regions spanning over 100 kb researchers have come up with the concept of variable chromatin modules (VCMs). The EU-funded CHROMISE project aims to determine VCM function and plasticity through a novel experimental and computational workflow that makes VCM identification fast and easy. Researchers will use the differentiation of mesenchymal stem cells as a model system and apply the generated knowledge to study genetic variants of metabolic diseases.
Objective
Most common disease-associated genetic variants are thought to fall into gene regulatory regions, where they affect the interaction between transcription factors (TFs) and DNA and induce transcriptional changes. To understand the extent of, and the mechanisms underlying variation in binding of TFs to DNA, genome-wide TF and chromatin state profiling studies were performed which revealed that non-coding variants frequently mediate coordinated changes in TF binding and chromatin mark enrichment over regions that span more than 100 kb. These regions were termed “variable chromatin modules” (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. However, little is known about the formation, function, or plasticity of VCMs. This is because vast amounts of epigenomics data have so far been required for identifying VCMs, making their identification costly, labour-intensive, and only applicable to easy-to-culture cell types. Recent work has demonstrated the value of ATAC-seq for defining regulatory element hierarchies that conceptually resemble VCMs. Here, I propose to extend these principles by developing an experimental and computational workflow for VCM identification using single-cell ATAC-seq. This will allow sample multiplexing for sequencing followed by genotype-based demultiplexing, thereby increasing throughput, minimizing sample input, and mitigating variation between samples (Aim 1). I will apply this workflow to study VCM plasticity during human mesenchymal stromal cell differentiation (Aim 2). The resulting data will be used to identify VCM-linked metabolic disease-relevant genetic variants, whose role in VCM formation will be validated using CRISPR-Cas9 (Aim 3).
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics epigenetics
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2020
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
1015 Lausanne
Switzerland
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.