Shaping the nucleus for transcriptional and developmental robustness

During embryogenesis, precise spatial-temporal patterns from transcription factors (TFs) establish the body plan of the embryo. These TFs function as master regulatory switches controlling genes that instruct cells to adopt specific morphologies and functions to form different organs, tissues, and body segments.

For example, TFs from the Homeobox (Hox) family specify the identity of individual body segments along the anterior-posterior axis. However, developmental genes targeted by Hox TFs such as shavenbaby (svb), which terminally fates cells in the ectoderm into trichomes, have enhancers controlled exclusively by low affinity binding sites for the Hox factor Ultrabithorax (Ubx). Moreover, live imaging experiments tracking TF binding in multicellular eukaryotes suggest that TF-DNA interactions are in general short-lived, lasting on average for only a few seconds. Given this stochastic and low-affinity molecular foundation, how can TFs drive efficient gene expression leading to robust phenotype development on the embryo?

My work using high- and super-resolution fluorescence microscopy in Drosophila melanogaster embryos showed that svb transcription sites reside in nuclear regions enriched for Ubx. These local environments are co-enriched for specific transcriptional cofactors, thus preserving both regulatory specificity and transcriptional efficiency. Epigenetic modifications, such as H3K4me1, also play an important role in preserving the integrity of these transcriptional microenvironments and regulatory specificity. Finally, genes co-regulated by the same TF can share and reinforce these transcriptional hubs, improving the robustness of gene expression and of phenotype development when embryos are subjected to environmental and genetic stresses.

Thus, understanding how the nuclear organization of TFs evolves during embryo development to form and maintain specialized transcriptional hubs, as well as how they can organize stochastic and transient molecular interactions into precise and robust regulatory signals will help decipher how multicellular eukaryotes physically organize their nuclei to shape gene expression.