Abstract
BackgroundDefining the transcriptome and the genetic pathways of pancreatic cells is of great interest for elucidating the molecular attributes of pancreas disorders such as diabetes and cancer. As the function of the different pancreatic cell types has been maintained during vertebrate evolution, the comparison of their transcriptomes across distant vertebrate species is a means to pinpoint genes under strong evolutionary constraints due to their crucial function, which have therefore preserved their selective expression in these pancreatic cell types.ResultsIn this study, RNA-sequencing was performed on pancreatic alpha, beta, and delta endocrine cells as well as the acinar and ductal exocrine cells isolated from adult zebrafish transgenic lines. Comparison of these transcriptomes identified many novel markers, including transcription factors and signaling pathway components, specific for each cell type. By performing interspecies comparisons, we identified hundreds of genes with conserved enriched expression in endocrine and exocrine cells among human, mouse, and zebrafish. This list includes many genes known as crucial for pancreatic cell formation or function, but also pinpoints many factors whose pancreatic function is still unknown. A large set of endocrine-enriched genes can already be detected at early developmental stages as revealed by the transcriptomic profiling of embryonic endocrine cells, indicating a potential role in cell differentiation. The actual involvement of conserved endocrine genes in pancreatic cell differentiation was demonstrated in zebrafish for myt1b, whose invalidation leads to a reduction of alpha cells, and for cdx4, selectively expressed in endocrine delta cells and crucial for their specification. Intriguingly, comparison of the endocrine alpha and beta cell subtypes from human, mouse, and zebrafish reveals a much lower conservation of the transcriptomic signatures for these two endocrine cell subtypes compared to the signatures of pan-endocrine and exocrine cells. These data suggest that the identity of the alpha and beta cells relies on a few key factors, corroborating numerous examples of inter-conversion between these two endocrine cell subtypes.ConclusionThis study highlights both evolutionary conserved and species-specific features that will help to unveil universal and fundamental regulatory pathways as well as pathways specific to human and laboratory animal models such as mouse and zebrafish.
Highlights
Defining the transcriptome and the genetic pathways of pancreatic cells is of great interest for elucidating the molecular attributes of pancreas disorders such as diabetes and cancer
By determining the transcriptome of endocrine cells from early stage embryos, we identified genes expressed during endocrine cell differentiation and putatively involved in this process; among them, myt1b and cdx4 are shown to be essential for endocrine cell differentiation in zebrafish
About 60 million of paired-end reads were obtained from each Illumina library, 80% of which mapped to the zebrafish genome
Summary
Defining the transcriptome and the genetic pathways of pancreatic cells is of great interest for elucidating the molecular attributes of pancreas disorders such as diabetes and cancer. No comprehensive interspecies comparison has been performed so far to define the conserved signatures for each pancreatic cell type, except for two studies comparing human and murine beta cells and reporting some notable differences between these two mammalian species [12, 21]. Comparative studies between evolutionary distant species are useful to identify the set of genes displaying highly conserved cell typespecific expression and likely playing a fundamental function in the studied cells Such analyses have not been performed yet on pancreatic cells due to the lack of transcriptomic data from pancreatic cells isolated from lower vertebrates such as zebrafish. Our list of pancreatic conserved genes represents a useful resource for studies related to pancreatic development and disease such as diabetes and pancreatic cancer
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