Project description
Research could uncover the regulatory mechanisms of microexons
Microexons are tiny exons that proved to have striking neuronal specificity established by their master splicing regulator Srrm4, which activates them during neuronal differentiation. The EU-funded NESTEDMICS project challenges this by supporting that microexon subclasses are dictated by their sensitivity to a close paralogue, Srrm3. Researchers will develop computational approaches and experiments using in vitro and in vivo systems to investigate how microexons are regulated. Project work could help answer how the different levels of the master regulators are controlled in each cell type and how the distinct sensitivities of microexons to Srrm3/4 are genomically encoded. Furthermore, it could also help explain how misregulation of the nested programmes affect human health, leading, for example, to diabetes and neurodevelopmental disorders.
Objective
Neural microexons are a paradigmatic example of a cell type-specific transcriptomic program. Microexons are tiny exons that we revealed to have striking neuronal specificity established by their master splicing regulator Srrm4, which activates them during neuronal differentiation.
However, our unpublished data challenge this on/off regulatory and functional paradigm. We found that a related paralog, Srrm3, is lowly but significantly expressed also in endocrine pancreas and, together with Srrm4, configure a 3-step switch of Srrm3/4 activity in pancreas (low), brain (mid) and retina (high). These different levels of expression activate increasingly larger subsets of microexons in the three tissues, configuring a triple-nested microexon program. Remarkably, initial results support a model in which microexon subclass inclusion is dictated largely by their sensitivity to Srrm3/4, and each subclass is differentially enriched for distinct functional categories including vesicle-mediated transport, neuronal differentiation and cilium biogenesis.
This project will assess the regulatory and functional architecture of this new paradigm by answering:
(1) How are the different levels of the master regulators controlled in each cell type?
(2) How are the distinct sensitivities of microexons to Srrm3/4 genomically encoded?
(3) What are the functional implications of the 'nestedness' of the microexon programs?
(4) How does misregulation of the nested programs contribute to disease?
These goals will be achieved by a combination of high-throughput methods and focused experiments using in vitro and in vivo systems. The expected results will provide a transformative multi-level portrait of microexons, from quantitative regulatory logic to organismal functions. Moreover, this novel paradigm is likely to apply to many other master regulators, expanding the impact of the project and shedding new light into how cell type-specific transcriptomes are established in embryogenesis.
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.
This project's classification has been human-validated.
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.
This project's classification has been human-validated.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Topic(s)
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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
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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.
ERC-COG - Consolidator Grant
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Call for proposal
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(opens in new window) ERC-2020-COG
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08002 Barcelona
Spain
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