Cells in multicellular organisms show a huge diversity of shape, size, and function, yet are all descended from the same totipotent zygote. As development progresses, cells lose their ability to contribute to different fates, instead committing to a narrower subset of expression programs. This stepwise reduction of differentiation potential has been illustrated in Waddington’s epigenetic landscape (“Waddington lineage”). The specific gene expression programs of cell types are governed by Core Regulatory Complexes (CoRCs), where transcription factors cooperate to maintain their own expression and the effector genes that give rise to the cellular phenotype. Cell types exist as terminal or transitory states of the Waddington lineage, and it is yet unclear whether and to what extent transitory developmental and terminal cell types involve similar or distinct regulatory principles and effector modules.
I will reconstruct the Waddington lineage of Platynereis dumerilii, an indirectly developing marine invertebrate with a wealth of transitory developmental and terminal cell types. I will gather single-cell RNA-seq and chromatin accessibility data for multiple developmental stages and computationally identify putative cell types. I will map these onto locations in the animal body using the in-situ expression patterns of lineage and cell type markers, and exploit unique electron microscopy data to explore the connection between gene expression and subcellular morphology. After connecting successive stages computationally, I will validate the resulting Waddington lineage with functional experiments, disrupting the expression of effector genes in the terminal cell types with CRISPR/Cas9.
By combining gene expression, chromatin accessibility, cellular lineage information, functional genomics, spatial localization, and, uniquely, subcellular morphology, we will shed light on animal development and the regulatory mechanisms that govern cell types.
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