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Single-cell epigenome analysis identifies transcriptional events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells [RNA-seq]

ABSTRACT: Cell fate can be reprogrammed by ectopic expression of lineage-specific transcription factors (TF). However, the exact cell state transitions during transdifferentiation are still poorly understood. Here, we have generated pancreatic exocrine cells of ductal epithelial identity from human fibroblasts using a set of six TFs. We mapped the molecular determinants of lineage dynamics using a factor-indexing method based on single-nuclei multiome sequencing (FI-snMultiome-seq) that enables dissecting the role of each individual TF and pool of TFs in cell fate conversion. We show that transition from mesenchymal fibroblast identity to epithelial pancreatic exocrine fate involves two deterministic steps: an endodermal progenitor state defined by activation of HHEX with FOXA2 and SOX17, and a temporal GATA4 activation essential for maintenance of pancreatic cell fate program. Collectively, our data suggest that transdifferentiation – although being considered a direct cell fate conversion method – occurs through transient progenitor states orchestrated by stepwise activation of distinct TFs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216854 | GEO | 2023/08/14

REPOSITORIES: GEO

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Project description:deBack2012 - Lineage Specification in Pancreas Development This model of two neighbouring pancreas precursor cells, describes the exocrine versus endocrine lineage specification process. To account for the tissue scale patterns, this couplet model has been extended to hundreds of coupled cells. This model is described in the article: On the role of lateral stabilization during early patterning in the pancreas de Back W., Zhou JX, Brusch L J. R. Soc. Interface 6 February 2013 vol. 10 no. 79 20120766 Abstract: The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development. This model is hosted on BioModels Database and identified by: MODEL1211010000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Single-cell epigenome analysis identifies transcriptional events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells [RNA-seq]

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