Changes to the identity of EndoC-\u03b2H1 beta cells may be mediated by stress-induced depletion of HNRNPD

Nicola Jeffery,Lorna W Harries,David Chambers,Ryan M Ames,Brandon M Invergo

doi:10.1186/s13578-021-00658-6

Nicola Jeffery, Lorna W Harries + Show 3 more

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https://doi.org/10.1186/s13578-021-00658-6

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Abstract

BackgroundBeta cell identity changes occur in the islets of donors with diabetes, but the molecular basis of this remains unclear. Protecting residual functional beta cells from cell identity changes may be beneficial for patients with diabetes.ResultsA somatostatin-positive cell population was induced in stressed clonal human EndoC-βH1 beta cells and was isolated using FACS. A transcriptomic characterisation of somatostatin-positive cells was then carried out. Gain of somatostatin-positivity was associated with marked dysregulation of the non-coding genome. Very few coding genes were differentially expressed. Potential candidate effector genes were assessed by targeted gene knockdown. Targeted knockdown of the HNRNPD gene induced the emergence of a somatostatin-positive cell population in clonal EndoC-βH1 beta cells comparable with that we have previously reported in stressed cells.ConclusionsWe report here a role for the HNRNPD gene in determination of beta cell identity in response to cellular stress. These findings widen our understanding of the role of RNA binding proteins and RNA biology in determining cell identity and may be important for protecting remaining beta cell reserve in diabetes.

Highlights

Beta cell identity changes occur in the islets of donors with diabetes, but the molecular basis of this remains unclear
We found cells in which heterogeneous nuclear ribonucleoprotein particle D (HNRNPD) expression had been reduced but which had not been exposed to any cellular stress showed a gain of somatostatin expression in ~ 4% of the culture, comparable to our previous findings in stressed cells (n = 4 p = 1.66 × 10–12; Fig. 3)
Cytokine-induced HNRNPD expression has been linked with increased rates of beta cell apoptosis in patients with diabetes [19], while reduced HNRNPD expression is linked to survival of pancreatic beta cells [25]

Summary

Introduction

Beta cell identity changes occur in the islets of donors with diabetes, but the molecular basis of this remains unclear. Protecting residual functional beta cells from cell identity changes may be beneficial for patients with diabetes. When the balance of homeostasis is disrupted, cellular stressors such as fluctuating glycaemia, dyslipidaemia, hypoxia or increased levels of inflammatory factors may become so prevalent that the viability or identity of cell populations may become compromised. This phenomenon occurs in multiple tissues, but is prevalent in tissues such as pancreatic islets that are directly involved in metabolic homeostasis [1].

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