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A transcriptional and open chromatin landscape and the role of ONECUT1 in human pancreas differentiation [ATAC-seq]

ABSTRACT: Pancreatic differentiation and specification of lineages is a tightly controlled process involving a interconnected network of transcriptional regulation. Although more knowledge on human pancreatic development is accumulating, the precise role of many transcription factors is only described in mouse. Therefore, it is of great interest to expand our knowledge using alternative model systems such as pancreatic in vitro differentiation of human pluripotent stem cells. Here, we provide stage-specific data from RNA-, ChIP-, and ATAC-sequencing to dissect transcriptional and regulatory mechanisms during pancreatic development. Transcriptome and open chromatin maps of pancreas differentiation from human pluripotent stem cells provide a stage-specific pattern of known pancreas transcription factors and determine ONECUT1 as a crucial regulator in pancreas progenitors. Moreover, our data suggest that ONECUT1 is also involved in preparing pancreatic progenitors for later endocrine specification.Our approach of dissecting the transcriptional and regulatory mechanisms revealed an important role for the specific key player ONECUT1 and will help to better understand human development and disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167596 | GEO | 2021/10/27

REPOSITORIES: GEO

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Project description:Understanding how distinct cell types arise from common multipotent progenitor cells is a major quest in stem cell biology. This knowledge will aid in the targeted differentiation and growth of stem cells, but also in the discovery of the basis of cellular plasticity and of how tissue programming can be controlled. The liver and pancreas share many aspects of their early development, being both specified in the same region of the endoderm, and, possibly, originating from a common progenitor. However, how pancreas versus liver cell fate decision occurs during embryogenesis and the molecular basis of this cellular plasticity are poorly understood. Here, we use RNA-Seq to define the molecular identity of liver and pancreas progenitors directly in mouse embryos and to investigate the mechanisms regulating the emergence of liver or pancreas as alternative fates from the endoderm. Progenitor cell-specific RNA was obtained from mouse Prox1-EGFP-labeled embryonic cells isolated by FACS at distinct developmental stages, before and after the onset of organogenesis. By integrating the temporal and spatial gene expression profiles, we found mutually exclusive signaling signatures in hepatic and pancreatic progenitors. Importantly, we identified the non-canonical Wnt pathway as a potential developmental regulator of the pancreas versus liver fate decision, being expressed in the foregut endoderm, before the cell fate choice is made, and then maintained in pancreas progenitors but absent in hepatic progenitors. Moreover, when assayed in Xenopus embryos, the non-canonical Wnt pathway is able to promote pancreatic fate and repress hepatic fate in the endoderm, suggesting an ancient mechanism for controlling pancreas versus liver fate choice. We expect that this knowledge will be key to formulate reprogramming strategies to convert adult hepatic cells into pancreatic cells as a cell-based therapeutic approach for diabetes. We performed sequencing-based expression profiling (RNA-Seq) of hepatic and pancreatic progenitors in the mouse at two distinct developmental stages.

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A transcriptional and open chromatin landscape and the role of ONECUT1 in human pancreas differentiation [ATAC-seq]

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