SUN-090 - JARID2, A Subunit of the Polycomb Repressive Complex 2, Contributes to Pituitary Development

Congenital Hypopituitarism (CH), occurring alone or as part of a midline structural birth defect, results in loss of hormones that are essential for growth, fertility, and metabolism. However, the genetic etiology of 84% of CH cases remains unknown. Mutations in genes encoding polycomb repressive complex 2 (PRC2) subunits diminish the repressive mark trimethylation on histone 3 lysine 27 (H3K27me3) and have been linked to human developmental disorders, including CH. Nonetheless, how H3K27me3 orchestrates pituitary development remains unknown. We established that H3K27me3 levels are low in murine Rathke’s pouch at embryonic day(e) 10.5 and increase in more differentiated anterior lobe cells (e12.5-e14.5). To determine the effect of reduced H3K27me3 in pituitary development, we focused on Jarid2, which is a subunit of PRC2 that is ubiquitously expressed during embryonic pituitary development. Our data show germline loss-of-function (LOF) mutation of Jarid2 (Jarid2mut/mut) causes pituitary stem cell hyperplasia, corticotrope hypoplasia, and no effect on the POU1F1 lineage at e14.5. To study the pituitary intrinsic role of Jarid2, we generated pituitary-specific Jarid2 LOF with Prop1T2AiCre (Jarid2Pitko/Pitko). These mice have pituitary stem cell hyperplasia at birth. To determine the gene expression and chromatin accessibility changes induced in these mutants, we performed single nucleus (sn) multi-omics on pituitaries from Jarid2Pitko/Pitko and their control littermates (N=3/genotype) at the onset of differentiation (e14.5). At this stage we observed no significant changes in the proportion of each cell type. Genes upregulated in Jarid2Pitko/Pitko pituitary progenitor clusters were associated with Gene Ontology terms for axon guidance, cell-cell adhesion, and neuron development. The sn Assay for Transposase-Accessible Chromatin using sequencing (snATACseq) revealed that Jarid2Pitko/Pitko mutants have increased chromatin accessibility in cell differentiation related genes. For example, elevated expression of the critical pituitary transcription factor Lhx3 is correlated with increased chromatin accessibility in intermediate progenitors in Jarid2Pitko/Pitko. Neither Jarid2mut/mut nor Jarid2Pitko/Pitko pituitaries have a change in the bulk level of H3K27me3 detected by immunohistochemistry, likely due to the ability of other PRC2 variants to catalyze this mark. In conclusion, we show that Jarid2 contributes to pituitary development by repressing pituitary stem cell proliferation and promoting differentiation into corticotropes. This study uncovered the mechanism of Jarid2 action as an epigenetic regulator of pituitary development, restricting chromatin accessibility in select target genes. This knowledge provides a foundation for understanding the epigenetic regulation of pituitary development.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*