Open AccessSingle-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation
Author(s) -
Chen Weng,
Jiajia Xi,
Haiyan Li,
Jian Cui,
Anniya Gu,
Sisi Lai,
Konstantin Leskov,
Luxin Ke,
Fulai Jin,
Yan Li
Publication year - 2020
Publication title -
nature metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.834
H-Index - 22
ISSN - 2522-5812
DOI - 10.1038/s42255-020-00314-2
Subject(s) - biology , directed differentiation , cellular differentiation , embryonic stem cell , enhancer , progenitor cell , cell fate determination , stem cell , computational biology , gene , microbiology and biotechnology , induced pluripotent stem cell , gene expression , genetics , transcription factor
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.