Bothma: Dynamics of transcription

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The Bothma group investigates how noncoding regions of the genome control gene expression in development by imaging transcription with single molecule resolution in real time.

How a single embryonic cell interprets its genome to give rise to the many diverse cell types that build an animal is one of nature’s enduring mysteries. Unravelling it promises to not only yield new insights into disorders of development and cancer, but also reveal the organizing principles of life. Even though we have uncovered all the regulatory factors and noncoding regions of the genome involved in specifying cell identity, we still don’t understand how these all come together to build an animal. One of the main reasons why this knowledge gap persisted is because until now we could not visualize a key degree of freedom – time.

Thanks to a recent series of innovations in live imaging the time is ripe for the introduction of a new paradigm in the study of embryogenesis based on how cell fates are established in living animals as development is actually taking place. We can now measure transcription factor concentration dynamics in individual cells, visualize transcription as it’s actually happening and even watch the binding of a single transcription factor molecule to DNA in a living embryo. Our experimental workhorse is the early Drosophila melanogaster embryo because of the ease of imaging and powerful genetic tools available in the system, but we are excited to expand into artificial vertebrate embryos and organoids in the future.

Method we use to image transcription and its regulation in space and time the early fly embryo. Scale bars in B) and C) are 25 and 10 microns, respectively.

The goal of the group is to understand how the noncoding parts of the genome drive cell fate decisions in development, by imaging the key molecular players mediating these decisions in their endogenous context in real time. This goal is underpinned by constantly developing new ground-breaking imaging and labelling technologies that empower us to visualize these processes in ways that have never been done before. These efforts will provide deep mechanistic insights into how regulatory DNA sequence encodes biological form and function, which will pave the way for us to understand how mutations in noncoding regions of the human genome cause disease.