Transient association of genes with RNA polymerase II clusters as a mechanism of gene regulation during early embryonic development

• Applicant: Professor Lennart Hilbert, Ph.D.
• Subject Area: Cell Biology ; Biophysics ; Developmental Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504473957

To maintain homeostasis and function, cells require precise control of the set of genes that are transcribed from DNA to RNA. In situations where cells undergo extensive rearrangements in their transcriptional behavior, formation of unusually large clusters of RNA polymerase II complexes has been observed. Recent results have led to a "hit-and-run" model, in which gene activation or silencing is achieved via transient association of the affected genes with these large polymerase II clusters. A more specific version of this model, the "condensate hit-and-run" model, proposes a key role of macromolecular assemblies behaving in a liquid-like fashion. In this research, we will examine to which extent the "hit-and-run" or the more specific "condensate hit-and-run" model is consistent with experimental observations, using super-resolution microscopy methods in the context of embryonic development. Our previous publications and preliminary work on early zebrafish embryo development provide evidence that a fraction of transcribed genes transiently "visit" the large polymerase II clusters. We have observed that, over the course of embryonic development, both the transcriptional activity and the visiting behavior of these genes change significantly. In our studies, we will use spontaneous changes in transcriptional activity, targeted experimental perturbations of transcriptional control, and state-of-the-art super-resolution microscopy methods to thoroughly scrutinize the two "hit-and-run" models of transcriptional control. Our results will contribute to gaining a mechanistic understanding of one of the central cell biological processes, the selective transformation of genetic information into cell type and cell function. This process is of critical importance, for instance in embryonic development, the emergence and treatment of cancer, and the human body's responses to adverse environmental influences.

• DFG Programme: Research Grants