Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes

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  • Tina Rönn
  • Jones K. Ofori
  • Alexander Perfilyev
  • Hamilton, Alexander
  • Karolina Pircs
  • Fabian Eichelmann
  • Sonia Garcia-Calzon
  • Alexandros Karagiannopoulos
  • Hans Stenlund
  • Anna Wendt
  • Petr Volkov
  • Matthias B. Schulze
  • Hindrik Mulder
  • Lena Eliasson
  • Sabrina Ruhrmann
  • Karl Bacos
  • Charlotte Ling
Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.
OriginalsprogEngelsk
Artikelnummer8040
TidsskriftNature Communications
Vol/bind14
Udgave nummer1
Antal sider21
ISSN2041-1723
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank the Nordic Network for Clinical Islet Transplantation (JDRF award 31-2008-413), Human Tissue Laboratory in EXODIAB/Lund University Diabetes Centre, Bioinformatics and Expression Analysis (BEA, supported by the Board of Research at the Karolinska Institute and the Research Committee at Karolinska Hospital) for microarray analysis, the Swedish Metabolomics Centre, Umeå University for metabolic profiling, Claes Wollheim and David Nicholls for valuable discussions, and Anna Hammarberg at MultiPark Cellomics Platform and Eugenia Cordero for technical assistance. EPIC array analysis was performed by the SNP&SEQ Technology Platform in Uppsala. The facility is part of the National Genomics Infrastructure (NGI) Sweden and Science for Life Laboratory. The SNP&SEQ Platform is also supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation. This study was supported by the Swedish Research Council (Dnr 2016-02486, 2018-02567, 2019-01406, 2014-2775, 2018-02435, and 2021-00628), Region Skåne, Strategic Research Area Exodiab (Dnr 2009-1039), the Novo Nordisk Foundation, the Swedish Foundation for Strategic Research (Dnr IRC15-0067), The European Research Council (ERC-Paintbox), the Diabetes Foundation, Kungliga Fysiografiska Sällskapet i Lund, the German Federal Ministry of Education and Research, and the State of Brandenburg to the German Center for Diabetes Research (82DZD00302, 82DZD03D03), as well as the Syskonen Svensson, Magnus Bergvall, Åke Wiberg, and Påhlsson Foundations.

Publisher Copyright:
© 2023, The Author(s).

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