OC5.6 - ECE_2863 - Defining the YAP/TEAD–SOX2–NFI network underlying pituitary stem cell maintenance and differentiation

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Abstract Resident stem cells in the anterior pituitary contribute to all hormone-secreting cell types throughout life and are essential for maintaining proper gland function. While pituitary stem cells (PSCs) are highly active during early postnatal stages, they become largely quiescent in adulthood, underscoring the requirement for tightly controlled transcriptional programs to balance stem cell maintenance and lineage commitment. Disruption of this balance can lead to pituitary dysfunction and disease; however, the molecular mechanisms governing pituitary stem cell fate decisions remain poorly understood. The transcriptional co-activator YAP, acting through TEAD transcription factors (TFs), has been established as a central regulator of PSC fate, promoting SOX2⁺ stem cell self-renewal and proliferation while repressing differentiation. Using an inducible YAP overexpression model combined with single-nuclei multiomic analyses, we have previously identified members of the Nuclear Factor I (NFI) family as candidate core regulators of PSC function. However, how NFIs influence PSC behaviour and how they integrate within the YAP/TEAD and SOX2 regulatory framework remains unclear. Here, we generated doxycycline-inducible SOX2 and NFI overexpression cell lines, alone and in combination, in pituitary-derived GH3 and LβT2 cells. Integration of RNA-seq and ATAC-seq analyses, complemented by immunofluorescence, revealed transcriptional and chromatin accessibility changes associated with pituitary lineage commitment. We show that SOX2 overexpression alone is sufficient to repress lineage-associated transcription factor programs at the transcript, chromatin and protein levels, whereas NFIs exert both shared and lineage-specific regulatory effects. Moreover, our data support a model in which YAP acts upstream to induce SOX2 expression, while NFIs function downstream of SOX2 to fine-tune lineage commitment. Together, these findings identify the YAP/TEAD–SOX2–NFI axis as a core regulatory network controlling the balance between PSC maintenance and differentiation. This axis provides a framework to better understand PSC regulation, with potential implications for regenerative and therapeutic strategies in the pituitary.

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