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Open AccessArticle

Bioinformatic Analyses of miRNA–mRNA Signature during hiPSC Differentiation towards Insulin-Producing Cells upon HNF4α Mutation

1
Department of Clinical Science, Faculty of Medicine, University of Bergen, 5021 Bergen, Norway
2
Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
3
Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway
*
Authors to whom correspondence should be addressed.
Present address: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Biomedicines 2020, 8(7), 179; https://doi.org/10.3390/biomedicines8070179
Received: 9 June 2020 / Revised: 22 June 2020 / Accepted: 24 June 2020 / Published: 27 June 2020
(This article belongs to the Special Issue Regenerative Medicine in Diabetes)
Mutations in the hepatocyte nuclear factor 4α (HNF4α) gene affect prenatal and postnatal pancreas development, being characterized by insulin-producing β-cell dysfunction. Little is known about the cellular and molecular mechanisms leading to β-cell failure as result of HNF4α mutation. In this study, we compared the miRNA profile of differentiating human induced pluripotent stem cells (hiPSC) derived from HNF4α+/Δ mutation carriers and their family control along the differentiation timeline. Moreover, we associated this regulation with the corresponding transcriptome profile to isolate transcript–miRNA partners deregulated in the mutated cells. This study uncovered a steep difference in the miRNA regulation pattern occurring during the posterior foregut to pancreatic endoderm transition, defining early and late differentiation regulatory windows. The pathway analysis of the miRNAome–transcriptome interactions revealed a likely gradual involvement of HNF4α+/Δ mutation in p53-mediated cell cycle arrest, with consequences for the proliferation potential, survival and cell fate acquisition of the differentiating cells. The present study is based on bioinformatics approaches and we expect that, pending further experimental validation, certain miRNAs deregulated in the HNF4α+/Δ cells would prove useful for therapy. View Full-Text
Keywords: miRNA; hiPSC; HNF4α; MODY1; insulin-producing cells; in-vitro differentiation; endocrine; progenitor; pancreas; pluripotent stem cells miRNA; hiPSC; HNF4α; MODY1; insulin-producing cells; in-vitro differentiation; endocrine; progenitor; pancreas; pluripotent stem cells
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Ghila, L.; Bjørlykke, Y.; Legøy, T.A.; Vethe, H.; Furuyama, K.; Chera, S.; Ræder, H. Bioinformatic Analyses of miRNA–mRNA Signature during hiPSC Differentiation towards Insulin-Producing Cells upon HNF4α Mutation. Biomedicines 2020, 8, 179.

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