Transcriptional activation by pioneer transcription factors in mammalian pre-implantation development

Venue: MSI Small Lecture Theatre, SLS

Abstract: 

Following fertilization, the totipotency is gradually decreased during cleavage divisions until reaching a pluripotent or differentiated state. During this process, transcription factors (TFs) play crucial roles in successful pre-implantation development. Notably, specialized TFs, called pioneer transcription factors (pTFs) have the unique ability to modulate epigenetic and chromatin states by recruiting chromatin remodelers and histone modifiers. Mammalian embryos are initially awakened during zygotic genome activation (ZGA) and further develop into blastocysts including three cell lineages. However, how pTFs/TFs control transcriptional regulation to achieve proper pre-implantation development is largely unknown.

The Orphan nuclear receptor Nr5a2 is expressed in murine embryos, but its function during pre-implantation development is unknown. Leveraging the low-input genomic approach, we discovered that Nr5a2 functions as a pTF that opens the chromatin during ZGA in mouse embryos (Gassler*, Kobayashi* et al., Science, 2022). The cryo-electron microscopy structure of the human NR5A2-nucleosome complex revealed its pioneering activity via minor groove anchor competition (Kobayashi et al., bioRxiv, 2023). We recently found that the chromatin binding of Nr5a2 is dynamically changed during the totipotency-to-pluripotency transition. Interestingly, Nr5a2 co-occupies regulatory elements with some lineage-determining factors at the morula stage (Kobayashi et al., in preparation). Taken together, my work provides insights into how pTFs regulate transcriptional and epigenetic states in mammalian embryos.

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