SFEBES2022 Poster Presentations Neuroendocrinology and Pituitary (72 abstracts)
Gene-chromatin regulatory circuits driving stemness in the anterior pituitary
Val Yianni 1 , Emily J. Lodge 1 , Thea L. Willis 1 , Yasmine Kemkem 1 , Michel Zamojski 2 , Natalia Mendelev 2 , Stuart C. Sealfon 2 , Frédérique Ruf-Zamojski 2 & Cynthia L. Andoniadou 1,3
1Centre for Craniofacial and Regenerative Biology, King’s College London, London, United Kingdom; 2Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, USA; 3Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität 29, Dresden, Germany
The pituitary gland is a dynamic organ that adapts its cellular architecture throughout life, making it an ideal model for the study of stem cells (SCs), their commitment and differentiation. Sox2-expressing cells are bona fide anterior pituitary stem cells (PSCs), which through genetic lineage tracing have been shown to give rise to all anterior pituitary hormone-producing cells both in the embryo and adult. The YAP/TAZ signalling pathway has been previously shown to promote PSC self-renewal, but the molecular mechanisms controlling this process remain unknown, as are additional key factors controlling the stem cell state. To explore these mechanisms, we utilised an inducible mouse model of YAP over-activation, mis-expressing constitutive active YAP in all endocrine cells of the anterior pituitary, compared to uninduced controls. In vivo, failure to downregulate YAP leads to PSC expansion, inability to upregulate lineage determining factors, and a subsequent failure of PSCs to differentiate. Pituitaries were dissociated and single cells sequenced using a multi-omic approach allowing simultaneous mRNA and global chromatin accessibility profiling for each individual cell. Individual cell types were identified based on gene and TF expression, as well as accessibility of TF binding motifs in the underlying DNA regions, thereby allowing characterisation of transcription dynamics. We present here the construction and analysis of gene-chromatin regulatory circuits predicted to be implicated in the regulation of PSC self-renewal. We focus on three members of the Nuclear Family I (NFI) family of TFs, previously undescribed in the pituitary gland, and identify these as putative regulators of PSCs in mice and humans. The study of novel PSC regulators is highly relevant to regenerative approaches, and to investigations on the underlying causes of disease including hypopituitarism and pituitary tumours.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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