Project Reference: TRG27-GRD-JA1

Project title: Decoding regulatory programmes that build an animal

Project outline

Starting from a single cell, an animal develops through differential interpretation of its genome sequence. Across development, regulatory programmes comprising transcription factors (TFs), regulatory elements and target genes control cell fate and state. While we are beginning to understand programmes in differentiated cell types, we know much less about the regulatory decisions that drive transitions between cell states and fates.

Single-cell multiomics can address this by measuring gene expression and chromatin accessibility across development. However, profiling is destructive. Because daughter cells cannot be assayed, regulatory transitions across individual cell divisions cannot be made.

C. elegans solves this probelem, because it develops through an invariant lineage. We can profile a mother cell from one embryo and its daughters from another, then connect their profiles through the lineage tree. We have generated the first lineage-resolved multiomic single-cell map in a developing animal and used it to predict regulatory programmes controlling early developmental transitions. These models predict which TFs act in particular cells, the regulatory elements they control and their target genes. The critical next step is to test whether these relationships are causal.

The student will select predicted regulators associated with cell-fate decisions and test their functions in vivo. Using genetic perturbation and single-cell multiomic profiling, they will determine which genes and regulatory regions respond when a TF is removed and whether affected cells retain their identity, adopt an alternative fate or enter a new state. Computational analyses will reconstruct altered developmental trajectories and refine the regulatory models. Selected regulatory elements will also be tested in vivo by mutating predicted TF binding sites in transgenic reporters.

Principal Supervisor

Professor Julie Ahringer

Email address: ja219@cam.ac.uk

Department / Partner Institute: Gurdon Institute

Website: https://www.ahringer.group.gurdon.cam.ac.uk/

BBSRC strategic theme

Understanding the rules of life