Journal
CELL
Volume 176, Issue 5, Pages 1158-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.12.029
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Funding
- EMBO long-term fellowship [ALTF 240-2014]
- VENI grant from the Netherlands Organization for Scientific Research (NWO-ZonMW) [016.166.119]
- HFSP fellowship [LT771/2015]
- VENI fellowship (NWO-ZonMW) [016.166.140]
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Homeostatic regulation of the intestinal enteroendocrine lineage hierarchy is a poorly understood process. We resolved transcriptional changes during enteroendocrine differentiation in real time at single-cell level using a novel knockin allele of Neurog3, the master regulator gene briefly expressed at the onset of enteroendocrine specification. A bi-fluorescent reporter, Neurog3Chrono, measures time from the onset of enteroendocrine differentiation and enables precise positioning of single-cell transcriptomes along an absolute time axis. This approach yielded a definitive description of the enteroendocrine hierarchy and its sub-lineages, uncovered differential kinetics between sub-lineages, and revealed time-dependent hormonal plasticity in entero-chromaffin and L cells. The time-resolved map of transcriptional changes predicted multiple novel molecular regulators. Nine of these were validated by conditional knockout in mice or CRISPR modification in intestinal organoids. Six novel candidate regulators (Sox4, Rfx6, Tox3, Myt1, Runx1t1, and Zcchc12) yielded specific enteroendocrine phenotypes. Our time-resolved single-cell transcriptional map presents a rich resource to unravel enteroendocrine differentiation.
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