Changes to the identity of EndoC-βH1 beta cells may be mediated by stress-induced depletion of HNRNPD

TY - JOUR

T1 - Changes to the identity of EndoC-βH1 beta cells may be mediated by stress-induced depletion of HNRNPD

AU - Jeffery, Nicola

AU - Chambers, David

AU - Invergo, Brandon M.

AU - Ames, Ryan M.

AU - Harries, Lorna W.

N1 - Funding Information: This work was supported by an Animal Free Research UK (AFRUK) Grant (AFR18-001) to LWH and a BBSRC/EPSRC Interface Innovation Fellowship (EP/S001352/1) to RMA. BMI was supported by a Wellcome Trust Institutional Strategic Support Award (204904/Z/16/Z). Funding Information: This work was supported by an Animal Free Research UK (AFRUK) Grant (AFR18-001) to LWH and a BBSRC/EPSRC Interface Innovation Fellowship (EP/S001352/1) to RMA. BMI was supported by a Wellcome Trust Institutional Strategic Support Award (204904/Z/16/Z). AFRUK are the UK?s leading non-animal biomedical research charity that exclusively funds promotes human-relevant research that replaces the use of animals. The authors would like to acknowledge the contribution of Dr. Raphael Scharfmann and INSERM for supplying the EndoC-?H1 cells used for this work. We would also like to thank Dr. Joe Burrage and Dr. Mark Russell for their guidance on FACS sorting of beta cells. Funding Information: This work was supported by an Animal Free Research UK (AFRUK) Grant (AFR18-001) to LWH and a BBSRC/EPSRC Interface Innovation Fellowship (EP/S001352/1) to RMA. BMI was supported by a Wellcome Trust Institutional Strategic Support Award (204904/Z/16/Z). AFRUK are the UK’s leading non-animal biomedical research charity that exclusively funds promotes human-relevant research that replaces the use of animals. The authors would like to acknowledge the contribution of Dr. Raphael Scharfmann and INSERM for supplying the EndoC-βH1 cells used for this work. We would also like to thank Dr. Joe Burrage and Dr. Mark Russell for their guidance on FACS sorting of beta cells. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12

Y1 - 2021/12

N2 - Background: 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. Results: A 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. Conclusions: We 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.

AB - Background: 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. Results: A 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. Conclusions: We 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.

KW - Beta-cells

KW - Cell differentiation

KW - HNRNPD

KW - RNA binding proteins

UR - http://www.scopus.com/inward/record.url?scp=85111298479&partnerID=8YFLogxK

U2 - 10.1186/s13578-021-00658-6

DO - 10.1186/s13578-021-00658-6

M3 - Article

AN - SCOPUS:85111298479

SN - 2045-3701

VL - 11

JO - Cell and Bioscience

JF - Cell and Bioscience

IS - 1

M1 - 144

ER -