PRC2 complex subunit JARID2 regulates embryonic pituitary stem cell differentiation to the POMC lineage

The pituitary is essential for growth, fertility, and stress response. Pituitary development is defined by transcription factor cascades, but how chromatin landscapes influence it remains elusive. JARID2 is a subunit of polycomb repressive complex 2 repressing transcription by depositing trimethylation on histone 3 lysine 27 (H3K27me3). Here, we established that H3K27me3 levels increase with differentiation in anterior pituitary from embryonic day (E) 10.5 to E14.5 despite ubiquitous Jarid2 mRNA expression. Germline loss of Jarid2 causes pituitary stem cell (PSC) hyperplasia and corticotrope hypoplasia without changing H3K27me3 bulk levels at E14.5. Pituitary-specific loss of Jarid2 with Prop1T2AiCre (Jarid2Pitko/Pitko) exhibits POMC lineage hypoplasia and PSC hyperplasia at E16.5. Pou1f1 or Nr5a1 lineages are not affected by Jarid2 mutation. To determine gene expression and chromatin accessibility changes in Jarid2Pitko/Pitko, we performed single nucleus (sn) multi-omics on E14.5 pituitaries. SnRNAseq revealed potential targets of Jarid2, including Meis2. SnATACseq revealed chromatin reprograming towards PSC retention rather than differentiation. Pax7 is reduced in both modalities in PSC. Together, we show that Jarid2 promotes stemness exit and POMC lineage differentiation, uncovering novel epigenetic regulation of pituitary development.