Abstract
The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Animals, Genetically Modified
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Cell Differentiation
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Cell Lineage
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Cell Proliferation
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Cells, Cultured
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Computational Biology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Databases, Genetic
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Embryonic Stem Cells / metabolism*
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Gene Expression Regulation, Developmental
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Gene Regulatory Networks
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Humans
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Mice, Inbred C57BL
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Multipotent Stem Cells / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Organogenesis
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Pancreas / embryology
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Pancreas / metabolism*
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Phenotype
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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RNA, Messenger / metabolism
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Signal Transduction*
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TEA Domain Transcription Factors
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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YAP-Signaling Proteins
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Zebrafish / embryology
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Zebrafish / genetics
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Zebrafish / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Nuclear Proteins
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Phosphoproteins
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RNA, Messenger
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TEA Domain Transcription Factors
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TEAD1 protein, human
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Transcription Factors
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YAP-Signaling Proteins
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YAP1 protein, human