Single-cell transcriptomics of East-Asian pancreatic islets cells

Rajkumar Dorajoo,Jianjun Liu,Jonathan Kang,Sudhagar Samydurai,Bernhard O Boehm,Vanessa S Y Tay,Yusuf Ali

doi:10.1038/s41598-017-05266-4

Abstract

Single-cell RNA-seq (scRNA-seq) of pancreatic islets have reported on α- and β-cell gene expression in mice and subjects of predominantly European ancestry. We aimed to assess these findings in East-Asian islet-cells. 448 islet-cells were captured from three East-Asian non-diabetic subjects for scRNA-seq. Hierarchical clustering using pancreatic cell lineage genes was used to assign cells into cell-types. Differentially expressed transcripts between α- and β-cells were detected using ANOVA and in silico replications of mouse and human islet cell genes were performed. We identified 118 α, 105 β, 6 δ endocrine cells and 47 exocrine cells. Besides INS and GCG, 26 genes showed differential expression between α- and β-cells. 10 genes showed concordant expression as reported in rodents, while FAM46A was significantly discordant. Comparing our East-Asian data with data from primarily European subjects, we replicated several genes implicated in nuclear receptor activations, acute phase response pathway, glutaryl-CoA/tryptophan degradations and EIF2/AMPK/mTOR signaling. Additionally, we identified protein ubiquitination to be associated among East-Asian β-cells. We report on East-Asian α- and β-cell gene signatures and substantiate several genes/pathways. We identify expression signatures in East-Asian β-cells that perhaps reflects increased susceptibility to cell-death and warrants future validations to fully appreciate their role in East-Asian diabetes pathogenesis.

Highlights

Data suggest that East-Asians may develop Type 2 diabetes (T2D) at a younger age and at lower BMI levels as compared to European ancestry populations[1, 2]
Ethnic differences in islet cell function may exist due to inherent genetics and epigenetic changes driven by varied lifestyles and is suggested to predispose Asian subjects to T2D4, 5
Hierarchical clustering of human islet cells using all transcripts with RPKM values ≥500 in ≥2% of cells [252 transcripts (146 genes)] revealed three main clusters based on known islet cell transcripts at GCG, INS and REG1A, indicating that cells captured were mainly pancreatic endocrine (α- and β-cells) and exocrine cells (Supplementary Figure 3)

Summary

Introduction

Data suggest that East-Asians may develop Type 2 diabetes (T2D) at a younger age and at lower BMI levels as compared to European ancestry populations[1, 2]. At the TCF7L2 locus)[3] Despite these accumulating genetic information, due to modest effect sizes conferred at these common T2D risk loci, major limitations still exists in clearly delineating the disease phenotype observed in East-Asians. Ethnic differences in islet cell function may exist due to inherent genetics and epigenetic changes driven by varied lifestyles and is suggested to predispose Asian subjects to T2D4, 5. As most human islet scRNA-seq studies have been performed predominantly in subjects of European ancestry, it is unclear if reported gene signatures are transferrable across ethnicities. We performed scRNA-seq on islet cells captured from three non-diabetic Singaporean Chinese subjects and aimed to evaluate for common and unique expression signatures with recent studies[7,8,9,10,11]

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Conclusion