Mechanisms and dynamics of gene expression during cellular differentiation and development

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PROJECT SUMMARY AND ABSTRACT Proper cellular differentiation is essential for healthy embryonic development, and new discoveries regarding cellular differentiation will impact the cancer, stem cell, and regenerative medicine fields. Caenorhabditis elegans is a nearly ideal model of cellular differentiation because the cell lineage is predictive and fully mapped from fertilization to adulthood (Sulston et al., 1977; Sulston et al., 1984). To determine molecular hallmarks that distinguish cells as they progress through early embryogenesis, we have generated a single-cell-resolution, whole-transcriptome RNA-seq (scRNA-seq) map of the C. elegans early embryo (Osborne Nishimura, et al., 2015; Tintori et al, 2016). Many developmental systems (human, mouse, etc) are also amenable to single-cell RNA-seq assays. However, it remains challenging in those organisms to conduct downstream research efforts aimed at dissecting the mechanisms critical for cellular differentiation and development. Because C. elegans affords more tractable genetics assays, microscopy, and quantification of cell fate changes, we aim to exploit the system to identify 1) mechanisms that pattern cell-specific transcriptomes prior to zygotic transcription, 2) the functional impact of mRNA dynamics on protein production and cellular differentiation, and 3) gene regulatory networks that orchestrate the first waves of cell-specific transcription and differentiation. Surprisingly, we have discovered fascinating sub-cellular localization patterns (e.g. nuclear, cell cortex, granules) in some asymmetrically partitioned mRNAs of the very early embryo. This presents us with a unique opportunity to study the link between mRNA localization, translational control, and developmental outcome in a system that is not confounded by nascent transcription. Our goal is to illuminate how systems biology approaches can inform our functional understanding of cellular differentiation and development in an intact living organism. !