Thoughts on Professor Wei Xie’s seminar “Decoding the transcription circuitry when life begins”
Deciphering the molecular beginnings of life is fraught with challenges, primarily due to the scarcity of embryonic material available for research. Prof. Wei Xie’s team has advanced our understanding by developing ultra-sensitive chromatin analysis technologies, enabling them to map the chromatin landscape and the transcription factors (TFs) circuitry during early embryonic development. Among their significant discoveries, the OBOX family of PRD-like homeodomain proteins stands out as pioneer transcription factors essential for zygotic genome activation (ZGA). Along with OBOX, the team also shed light on the roles of NR5A2, a nuclear receptor, and TFAP2C, a regulator known for its involvement in trophectoderm formation, linking ZGA to the earliest lineage segregation in totipotent mouse embryos.
The exploration of the OBOX gene family’s role in ZGA marks a breakthrough, despite the complexity posed by the family’s genetic redundancy, where multiple members can compensate for each other’s absence. Deletion of a large genomic region encompassing most OBOX genes leads to a 2-cell to 4-cell developmental arrest and impaired ZGA. To further characterize individual members’ functions, Prof. Xie’s team categorized the members into maternally transcribed and zygotically expressed, and found that reintroducing either type could rescue both development and transcriptional activity. Additionally, the team discovered that OBOX proteins specifically bind to regulatory sequences of CG-poor ZGA genes, recruiting RNA polymerase II to activate transcription. While these insights are pivotal, they are derived from mouse models. This prompts questions about the transferability of these findings to human development, which will be interesting areas for future exploration. Moreover, while the role of the OBOX family in RNA polymerase II loading is clearer, the mechanisms governing its unloading are not yet understood. Unraveling this aspect could provide further insight into the regulation of gene expression during the early stages of life and shed light on the molecular interactions that enable a fertilized egg to embark on the path to a fully developed organism.
