Revealing the Key Regulators of Cell Identity in the Human Adult Pancreas

Vanheer, Lotte; Schiavo, Andrea Alex; Van Haele, Matthias; Haesen, Tine; Janiszewski, Adrian; Chappell, Joel; Roskams, Tania; Cnop, Miriam; Pasque, Vincent

Cellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies key regulators of cell identity in the human adult pancreas. We predict that HEYL and JUND are active in acinar and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell-derived pancreatic cells. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity in the human adult pancreas. Furthermore, given that transcription factors are major regulators of embryo development and are often perturbed in diseases, a comprehensive understanding of how transcription factors work will be relevant in development and disease biology. HIGHLIGHTS - Reconstruction of gene regulatory networks for human adult pancreatic cell types - An interactive resource to explore and visualize gene expression and regulatory states - Predicting putative transcription factors driving pancreatic cell identity - HEYL and JUND as candidate regulators of acinar and alpha cell identity, respectively