The core clock transcription factor BMAL1 drives circadian β-cell proliferation during compensatory regeneration of the endocrine pancreas

Volodymyr Petrenko, Miri Stolovich-Rain, Bart Vandereycken, Laurianne Giovannoni, Kai Florian Storch, Yuval Dor, Simona Chera, Charna Dibner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Circadian clocks in pancreatic islets participate in the regulation of glucose homeostasis. Here we examined the role of these timekeepers in β-cell regeneration after the massive ablation of β cells by doxycycline-induced expression of diphtheria toxin A (DTA) in Insulin-rtTA/TET-DTA mice. Since we crossed reporter genes expressing α- and β-cellspecific fluorescent proteins into these mice, we could follow the fate of α- and β cells separately. As expected, DTA induction resulted in an acute hyperglycemia, which was accompanied by dramatic changes in gene expression in residual β cells. In contrast, only temporal alterations of gene expression were observed in α cells. Interestingly, β cells entered S phase preferentially during the nocturnal activity phase, indicating that the diurnal rhythm also plays a role in the orchestration of β-cell regeneration. Indeed, in arrhythmic Bmal1-deficient mice, which lack circadian clocks, no compensatory β-cell proliferation was observed, and the β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia, and fatal diabetes.

Original languageAmerican English
Pages (from-to)1650-1665
Number of pages16
JournalGenes and Development
Volume34
Issue number23-24
DOIs
StatePublished - 1 Dec 2020

Bibliographical note

Funding Information:
We thank the colleagues from the University of Geneva—Ueli Schibler, Jacques Philippe, and Claes Wollheim—for constructive discussions; Marie-Claude Brulhart-Meynet for skillful technical assistance; Mylène Docquier, Céline Delucinge-Vivier, Didier Chollet, Emmanouil Dermitzakis, Luciana Romano, Deborah Bielser, Cédric Howald, and Keith Harshman for conducting RNA sequencing; Jean-Pierre Aubry-Lachainaye for help with cell sorting; and Charles Weitz from Harvard Medical School for generously sharing the Bmal1st/st mouse strain. This work was funded by Swiss National Science Foundation grants 31003A_166700/1, and 310030_184708/1; European Foundation for the Study of Diabetes/Novo Nordisk Programme for Diabetes Research; the Vontobel Foundation; the Novartis Consumer Health Foundation; the Bo and Kerstin Hjelt Foundation for diabetes type 2; the Swiss Life Foundation; the Olga Mayenfisch Foundation (to C.D.); University of Geneva-The Hebrew University of Jerusalem Joint Seed Money Funding Scheme (to Y.D. and C.D.); Research Council of Norway (NFR 251041, SC); and the Novo Nordic Foundation (NNF15OC0015054 to S.C.).

Funding Information:
We thank the colleagues from the University of Geneva-Ueli Schibler, Jacques Philippe, and Claes Wollheim-for constructive discussions; Marie-Claude Brulhart-Meynet for skillful technical assistance; Myl?ne Docquier, C?line Delucinge-Vivier, Didier Chollet, Emmanouil Dermitzakis, Luciana Romano, Deborah Bielser, C?dric Howald, and Keith Harshman for conducting RNA sequencing; Jean-Pierre Aubry-Lachainaye for help with cell sorting; and Charles Weitz from Harvard Medical School for generously sharing the Bmal1st/st mouse strain. This work was funded by Swiss National Science Foundation grants 31003A_166700/1, and 310030_184708/1; European Foundation for the Study of Diabetes/Novo Nordisk Programme for Diabetes Research; the Vontobel Foundation; the Novartis Consumer Health Foundation; the Bo and Kerstin Hjelt Foundation for diabetes type 2; the Swiss Life Foundation; the Olga Mayenfisch Foundation (to C.D.); University of Geneva-The Hebrew University of Jerusalem Joint Seed Money Funding Scheme (to Y.D. and C.D.); Research Council of Norway (NFR 251041, SC); and the Novo Nordic Foundation (NNF15OC0015054 to S.C.).

Publisher Copyright:
© 2020 Petrenko et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

Keywords

  • Circadian clockwork
  • Diabetes
  • Glucose metabolism
  • Insulin-rtTA/TET-DTA mouse model
  • Pancreatic α and β cells
  • β-cell proliferation
  • β-cell regeneration

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