Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
DNA methylation directs functional maturation of pancreatic β cells
Sangeeta Dhawan, … , Aleksey Matveyenko, Anil Bhushan
Sangeeta Dhawan, … , Aleksey Matveyenko, Anil Bhushan
Published June 22, 2015
Citation Information: J Clin Invest. 2015;125(7):2851-2860. https://doi.org/10.1172/JCI79956.
View: Text | PDF
Research Article Development Endocrinology Genetics Metabolism

DNA methylation directs functional maturation of pancreatic β cells

  • Text
  • PDF
Abstract

Pancreatic β cells secrete insulin in response to postprandial increases in glucose levels to prevent hyperglycemia and inhibit insulin secretion under fasting conditions to protect against hypoglycemia. β cells lack this functional capability at birth and acquire glucose-stimulated insulin secretion (GSIS) during neonatal life. Here, we have shown that during postnatal life, the de novo DNA methyltransferase DNMT3A initiates a metabolic program by repressing key genes, thereby enabling the coupling of insulin secretion to glucose levels. In a murine model, β cell–specific deletion of Dnmt3a prevented the metabolic switch, resulting in loss of GSIS. DNMT3A bound to the promoters of the genes encoding hexokinase 1 (HK1) and lactate dehydrogenase A (LDHA) — both of which regulate the metabolic switch — and knockdown of these two key DNMT3A targets restored the GSIS response in islets from animals with β cell–specific Dnmt3a deletion. Furthermore, DNA methylation–mediated repression of glucose-secretion decoupling genes to modulate GSIS was conserved in human β cells. Together, our results reveal a role for DNA methylation to direct the acquisition of pancreatic β cell function.

Authors

Sangeeta Dhawan, Shuen-Ing Tschen, Chun Zeng, Tingxia Guo, Matthias Hebrok, Aleksey Matveyenko, Anil Bhushan

×

Figure 1

DNA methylation directs metabolic programming during β cell maturation.

Options: View larger image (or click on image) Download as PowerPoint
DNA methylation directs metabolic programming during β cell maturation.
...
(A) Relative mRNA expression of indicated genes in sorted β cells from P4 and P25 MIP-GFP mice. Cyclophilin A was used as a housekeeping gene. n = 3 independent experiments. Error bars represent SEM. *P < 0.05, **P < 0.01, Student’s t test. (B) Bisulfite sequencing analysis for the Hk1 and Ldha loci at indicated regions comparing sorted β cells from P4 and P25 MIP-GFP mice (representative clones from n = 3 mice). Each horizontal line with dots is an independent clone, and 10 clones are shown here. These regions are almost fully DNA methylated (filled circles) in β cells from P25 mice, but largely hypomethylated (open circles) in β cells from P4 mice.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts