TY - JOUR TI - Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation AU - Weng, Chen AU - Xi, Jiajia AU - Li, Haiyan AU - Cui, Jian AU - Gu, Anniya AU - Lai, Sisi AU - Leskov, Konstantin AU - Ke, Luxin AU - Jin, Fulai AU - Li, Yan T2 - Nature Metabolism AB - The in vitro differentiation of insulin-producing beta-like cells can model aspects of human pancreatic development. Here, we generate 95,308 single-cell transcriptomes and reconstruct a lineage tree of the entire differentiation process from human embryonic stem cells to beta-like cells to study temporally regulated genes during differentiation. We identify so-called ‘switch genes’ at the branch point of endocrine/non-endocrine cell fate choice, revealing insights into the mechanisms of differentiation-promoting reagents, such as NOTCH and ROCKII inhibitors, and providing improved differentiation protocols. Over 20% of all detectable genes are activated multiple times during differentiation, even though their enhancer activation is usually unimodal, indicating extensive gene reuse driven by different enhancers. We also identify a stage-specific enhancer at the TCF7L2 locus for diabetes, uncovered by genome-wide association studies, that drives a transient wave of gene expression in pancreatic progenitors. Finally, we develop a web app to visualize gene expression on the lineage tree, providing a comprehensive single-cell data resource for researchers studying islet biology and diabetes. DA - 2020/11/30/ PY - 2020 DO - 10.1038/s42255-020-00314-2 DP - www.nature.com SP - 1 EP - 16 LA - en SN - 2522-5812 UR - https://www.nature.com/articles/s42255-020-00314-2 Y2 - 2020/12/01/17:35:38 ER -