The regulation of gene expression during vertebrate embryogenesis
A defining feature of complex multicellular organisms is their ability to generate multiple cell types with specific phenotypes and behaviors. During development, this process must be precisely coordinated in time and space through the generation of cell-specific transcriptional programs. In the adult organism, specific transcriptional programs also influence tissue homeostasis by controlling processes such as cell turnover, behavior and physiological status. Thus, a critical question in both development and physiology is how the decision to transcribe a gene at a given level is controlled.
Upon fertilization, the genome of animal embryos remains transcriptionally inactive until the controlled onset of transcription during the maternal-zygotic transition (MZT). A key factor in regulating this transition is the accessibility of the genome for DNA binding proteins. Therefore, determining how the transcriptional machinery operates in the context of a changing nuclear landscape is central to understanding how any region of the genome becomes transcriptionally competent. Subsequently, changes in chromatin structure (2D) and nuclear architecture (3D) similarly influence local transcriptional competence in specific regions of genome. Thus, understanding the interplay between chromatin structure, nuclear architecture and the transcriptional machinery will allow us to build a model of global and local transcriptional control in the dynamic context of development and homeostasis.
Currently, we focus on the genome-wide onset of transcription, with the aim to understand how the transcriptional machinery and chromatin template are brought together in time and space to robustly regulate transcription in hundreds of blastomeres during genome activation. This includes the development of tools to visualize chromatin architecture at high resolution, quantitatively analyze protein levels and transcriptional output, and study the interaction between chromatin and transcriptional machinery at high resolution. Our long-term goal is to then use this knowledge to improve our understanding of more complex changes in gene expression, as for example observed when cells transition from pluripotency to lineage specification and during reprogramming. Because the principles that regulate global (genome-wide) and local (gene-specific) changes in gene expression are fundamentally similar, we will apply accrued knowledge and technologies to answer the long standing question how cells become different from one another. We mostly use zebrafish embryos because they provide an excellent model to perform our studies in a single, developmentally relevant context.
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