Gene regulatory networks governing pancreas development

Abstract

Elucidation of cellular and gene regulatory networks (GRNs) governing organ development will accelerate progress toward tissue replacement. Here, we have compiled reference GRNs underlying pancreas development from data mining that integrates multiple approaches, including mutant analysis, lineage tracing, cell purification, gene expression and enhancer analysis, and biochemical studies of gene regulation. Using established computational tools, we integrated and represented these networks in frameworks that should enhance understanding of the surging output of genomic-scale genetic and epigenetic studies of pancreas development and diseases such as diabetes and pancreatic cancer. We envision similar approaches would be useful for understanding the development of other organs.

Figure 1. Pancreas cell lineage and gene regulatory motifs in development

(A) Current lineage model of pancreatic cell differentiation. Key factors that mark each lineage are: FoxA2 - definitive endoderm, Pdx1/Ptf1a/Sox9/Nkx6.1 - multipotent progenitor, Nkx6.1/Sox9 - bipotent progenitor, Ptf1a - pro-acinar and acinar cell, Neurog3 - endocrine progenitor, Sox9 - duct cell, Nfatc1/Ins - β-cells, Arx/Gcg - α-cell. (B) Sub-circuits of pancreas gene regulatory network representing canonical network motifs. (C) Pancreatic progenitor gene regulatory network. Pink nodes - transcription factors, yellow nodes - effector genes, black lines - positive/inductive relation, red lines - negative/inhibitory relation.

Figure 2. Gene regulatory network of differentiating acinar cells

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Figure 3. Endocrine progenitor gene regulatory network

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Figure 4. Immature β-cell gene regulatory network

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Figure 5. Adult β-cell gene regulatory network

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