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Constraint, Adaptation, and Heterogeneity: Genomic and single-cell approaches to understanding the evolution of developmental gene regulatory networks

Project description

The unassuming sea urchin sheds light on the evolution of development and its regulators

Development is a complex and highly regulated process. Among the regulators of gene expression are DNA regulatory elements like promoters and enhancers. Mutations in regulators play a role not only in disease states but also in evolution of new morphologies. In this way, understanding the evolution of developmental gene regulatory networks is a critical piece of the development puzzle. The EU-funded evolSingleCellGRN project is applying advanced single-cell methodologies in the sea urchin, including a recently developed assay of chromatin accessibility (ATAC-Seq) that points to areas 'open' to binding and thus regulation. It facilitates the study of epigenetic modifications on a genome-wide scale. Identifying tissue-specific regulatory elements and evaluating effects when they are mutated should shed light on how development evolves.

Objective

Cell types in development arise from precise patterns of gene expression driven by differential usage of DNA regulatory elements. Mutations affecting these elements, or proteins binding them, are major contributors to disease and underlie the evolution of new morphologies. To better understand these elements and how they evolve, I introduce a set of single-cell RNA and ATAC-Seq sequencing technologies that: A) Identify tissue-specific regulatory elements and expression profiles by interrogating individual cells, B) Allow for a precise read-out of developmental responses to mutation and perturbation, including cell-fate re-specification, C) Lead to the development of a regulatory-information based concept of homology that will be used to understand developmental evolution. The research makes use of sea urchins. The well-annotated sea urchin regulatory network, a detailed understanding of inductive interactions in early development, and an active body of evolutionary research justify this choice. Using single-cell ATAC-Seq and a new method for resolving single-cell, nascent transcripts, I will build a detailed atlas of sea urchin development and use this atlas to understand how regulatory landscapes change during specification and how they evolve between closely related species. I will also investigate, at single-cell resolution, how larval skeletal cells are regenerated following the loss of a cell lineage that mirrors euechinoid evolution. To better understand the origins of cell types in sea urchins, I will characterize embryos of the cnidarian Nematostella, using shared regulatory sites to define cell types which I will compare to urchins and my previous work in Drosophila. The work will generate single-cell methods for non-traditional model systems and help to resolve the processes by which, and the paths along which, development evolves.

Keywords

Host institution

HUMBOLDT-UNIVERSITAET ZU BERLIN
Net EU contribution
€ 1 499 900,00
Address
UNTER DEN LINDEN 6
10117 Berlin
Germany

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Region
Berlin Berlin Berlin
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 1 499 900,00

Beneficiaries (1)