Vanheer Lotte, Fantuzzi Federica, To San Kit, Schiavo Andrea, Van Haele Matthias, Ostyn Tessa, Haesen Tine, Yi Xiaoyan, Janiszewski Adrian, Chappell Joel, Rihoux Adrien, Sawatani Toshiaki, Roskams Tania, Pattou Francois, Kerr-Conte Julie, Cnop Miriam, Pasque Vincent
Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium.
ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium.
NAR Genom Bioinform. 2023 Jul 10;5(3):lqad068. doi: 10.1093/nargab/lqad068. eCollection 2023 Sep.
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 regulators of cell identity and cell states in the human adult pancreas. We predict that HEYL, BHLHE41 and JUND are active in acinar, beta 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 (hiPSC)-derived islet cells. Using single-cell transcriptomics, we found that JUND represses beta cell genes in hiPSC-alpha cells. BHLHE41 depletion induced apoptosis in primary pancreatic islets. 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 and cell states in the human adult pancreas.
发育过程中的细胞身份受形成基因调控网络的转录因子控制。然而，人类成年胰腺中细胞身份背后的转录因子和基因调控网络在很大程度上仍未被探索。在这里，我们整合了人类成年胰腺的多个单细胞RNA测序数据集，共计7393个细胞，并全面重建了基因调控网络。我们表明，由142个转录因子组成的网络形成了表征胰腺细胞类型的不同调控模块。我们提供的证据表明，我们的方法可识别人类成年胰腺中细胞身份和细胞状态的调节因子。我们预测HEYL、BHLHE41和JUND分别在腺泡细胞、β细胞和α细胞中活跃，并表明这些蛋白质存在于人类成年胰腺以及人类诱导多能干细胞（hiPSC）衍生的胰岛细胞中。使用单细胞转录组学，我们发现JUND在hiPSC-α细胞中抑制β细胞基因。BHLHE41的缺失诱导了原代胰腺胰岛细胞的凋亡。可在网上交互式地探索这个全面的基因调控网络图谱。我们预计我们的分析将成为更深入剖析转录因子如何调节人类成年胰腺中细胞身份和细胞状态的起点。
