Uncovering how the genome directs development

Uncovering how the genome directs development

Prof Julie Ahringer; University of Cambridge

Julie Ahringer is a group leader in the Gurdon Institute and a Professor in Genetics at the University of Cambridge, where she investigates transcription and chromatin regulation in development. A major focus is the application of single-cell multiomic profiling in C.elegans to decipher the genome regulatory changes that drive developmental decisions across complete developmental trajectories. Her group also pioneered genome-wide RNAi screening, carrying out the first systematic inactivation of genes in any animal by creating the widely-used C. elegans RNAi feeding library.

Multimodal single-cell profiling provides a powerful approach for unravelling the gene regulatory mechanisms that drive development, by simultaneously capturing cell-type-specific transcriptional and chromatin states. However, its inherently destructive nature hampers the ability to trace regulatory dynamics between mother and daughter cells. Taking advantage of the invariant cell lineage of Caenorhabditis elegans, we constructed a lineage-resolved single-cell multimodal map of development up to gastrulation, which allows the tracing of chromatin accessibility and gene expression changes across cell divisions and regulatory cascades. Through analysing the map, we find that zygotic transcription begins on a pre-patterned accessible chromatin landscape, identified regulators that drive zygotic genome activation, and defined transcriptional cascades during early lineage specification. Our findings demonstrate the power of a lineage-resolved atlas for dissecting the genome regulatory events of development. I will also discuss a large heterochromatin genetic interaction screen, which led to our finding that indirect activation of stress pathways is a major contributor to heterochromatin dysfunction phenotypes.

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