How to “Run” embryonic development

The term “embryonic development” was originally proposed some 2,400 years ago by Aristotle, however, many aspects of how the genome regulates development remain unclear. One major challenge of the modern Genomics Era is to better understand how transcriptional factors, transcriptional activators and repressors, regulate gene expression in order to support spatiotemporal outputs that change over the course of development. Recently, Dr. Theodora Koromila – senior postdoc in the Stathopoulos lab, together with Dr. Angelike Stathopoulos, at the California Institute of Technology, took a different approach to gene regulation by focusing mostly on transcriptional repressors. Using the quantitative MS2-MCP live imaging technology, they have provided insight into the mechanisms of action of the broadly-expressed transcriptional factors Runt (Run; Runx ortholog) and Suppressor of Hairless [Su(H)], throughout the early Drosophila embryo.

Specifically, based on the predicted transcriptional factors binding sites, both of these proteins were identified in an enhancer of the BMP antagonist gene short-gastrulation (sog) called the sog_Distal enhancer. Upon mutagenesis of these binding sites, the reporter-driven expression patterns exhibit dynamic spatiotemporal width changes. To assess these phenotypes systematically, Koromila and Stathopoulos devised a MS2-MCP live imaging approach to measure the spatiotemporal outputs across the entire embryo (see Movie). In this context, when the Run binding site was mutated, active expression was detected earlier than in the control. This suggests that Run normally acts to regulate the timing of transcription (see Graphical Abstract). Furthermore, their data demonstrated that Su(H) regulates expression levels, and that both factors control spatial expression. On the other hand, whereas Su(H) functions as a dedicated repressor, Run temporally switches its activity from repressor to activator in the context of the sog_Distal enhancer (see Graphical Abstract).

This research has just been published in the scientific journal Cell Reports (https://doi.org/10.1016/j.celrep.2019.06.063) and demonstrates that broadly-expressed repressors not only contribute to dynamic gene expression, but also play temporally-distinct roles. These findings provide an important basis for future research on how broadly-acting transcription factors control gene expression, which will likely be applicable to higher organisms, including vertebrates, as cis-regulatory mechanisms are generally conserved in metazoans.

The full study, “Distinct roles of broadly-expressed repressors support dynamic enhancer action and change in time” appears in Cell Reports (July 2019).

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