(W1100) DECIPHER TEMPORAL CONTROL OF GENE REGULATION DURING HEALTHY AND DISEASED THYMIC ORGANOGENESIS USING 22q11DS HUMAN INDUCED PLURIPOTENT STEM CELL MODEL
Abstract: The main function of the thymus is to mature and select T cells against self and foreign antigens. Failure in this process can lead to autoimmunity or immuno-deficiency. In 22q11 Deletion Syndrome (22q11DS), the most common human copy number variant, patients present with a broad phenotypic spectrum of immune defects. In severe cases, patients are born athymic with high morbidity and mortality. The immune defects in 22q11DS have been largely attributed to the deletion of a copy of transcription factor T-box 1 (TBX1). However, how the monoalleic deletion leading to dysregulation of retionic acid singaling and microRNA processing and perturbs thymic morphogenesis is unknown. In this study, we aimed to decipher the precise temporal control of gene regulation during healthy and diseased thymic organogenesis using a human induced pluripotent stem cell model and multi-omics approaches.
Using a platform that generates functional thymic organoids by recapitulating key stages of thymic epithelial differentiation in vitro, we have generated 22q11DS thymic organoids that mimic transcriptomes of 22q11DS thymic differentiation. Single-cell transcriptomic analysis revealed striking differences in the expression of genes regulatory networks govering development, retinoic acid signaling and microRNA processing at the third pharyngeal pouch stage. Our ongoing work aims to study transcriptomic differences caused by dysregulation of retinoic acid signaling and microRNA processing leading to failure of thymic organogenesis.
