Combining developmental biology and genomics to decode the mechanisms of gene regulation.
In the Giraldez Lab, we study the regulatory code that governs gene expression during vertebrate development after fertilization. We study this problem from four angles. First, we look at how Genome Activation takes place in the embryo during the maternal-to-zygotic transition combining super resolution imaging approaches and genomics . Next, we identify regulatory elements that drive post-transcriptional regulation of activated genes. Third, we pioneer molecular and computational methods to understand how these elements are integrated to shape global gene expression. Additionally, this knowledge is applied to engineer novel therapeutic mRNAs for gene therapy and improve vaccine development.
We identified three key maternal transcription factors – Nanog, Sox19b (Sox2) and Pou5f3 (Oct4) – as widespread regulators of gene activation during the maternal-to-zygotic transition in zebrafish (Lee, Bonneau, et al. Nature 2013). We now study the molecular mechanisms by which the genome gains competence for transcriptional activation during this fundamental transition in biology (Chan et al. Developmental Cell 2019 and Miao, Tang, et al. Mol Cell 2022).
Using zebrafish and human cell lines, we apply functional genomics to understand the post-transcriptional regulatory code in vertebrates. Our investigations span RNA stability (Giraldez et al. Science 2006)), RNA modifications (Kontur et al. Cell Rep 2020), RNA structure (Beaudoin et al. Nat Struct Mol Biol 2018), RNA binding proteins and their recognition sequences, upstream ORFs, and translational regulation (Bazzini et al. EMBO J. 2016).
The design of therapeutic mRNAs relies heavily on our understanding of post-transcriptional regulatory mechanisms, which play a key role in determining mRNA stability, translation efficiency, and tissue-specific expression. In our lab, we apply and develop cutting-edge high-throughput methods, such as massively parallel reporter assays and ribosome profiling, to systematically uncover the regulatory elements that can be optimized for therapeutic applications (Strayer et al. bioRxiv 2023, Musaev et al. Cell Rep 2024, Yartseva et al. Nat Methods 2017, Vejnar et al. Genome Res 2019, Beaudoin et al. Nat Struct Mol Biol 2018, Bazzini et al. EMBO J 2016, Johnstone et al. EMBO J 2016). We combine these efforts with computational approaches to model mRNA behavior in different cellular contexts, and to enable the design of highly stable, tissue-specific, and efficient mRNA therapies. Our ultimate goal is to integrate this knowledge into a predictive framework for engineering mRNAs that can precisely target disease-related pathways while minimizing off-target effects, advancing the field of gene therapy and vaccine development.
Post-transcriptional regulation is critically important in determining cellular phenotypes and behavior, particularly during early development when the genome is transcriptionally silent. We apply and pioneer novel high-throughput methods to elucidate regulatory networks at the system level (Yartseva, Takacs, et al. Nat Methods. 2016 and Vejnar, Abdel Messih, Takacs, Yartseva, et al. Genome Res 2019).
