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Modulation of DNA Methylation as a Treatment for Diabetes?

Review of "DNA methylation status correlates with adult β-cell regeneration capacity" from NPJ Regenerative Medicine by Stuart P. Atkinson

Aristaless related homeobox (Arx) and Paired box gene 4 (Pax4) represent key transcription factors involved in the specification of pancreatic α- and β- cell fates, respectively [1]. Interestingly, previous research led by Keith Al-Hasani and Assam El-Osta (Monash University, Melbourne, VIC, Australia) demonstrated that the deletion of Arx or the induced overexpression of Pax4 prompted the regeneration and conversion of pancreatic α-cells into functional insulin-producing β-like cells [2, 3].

To understand the mechanisms that underpin this direct lineage conversion, which may support the development of effective treatments for diabetes, the authors recently undertook an evaluation of the DNA methylation profiles of the Neurogenin3 (Ngn3) and Sox11 genes during the induced conversion of pancreatic α-cells into β-cells [4]. While Ngn3 represents a master regulator of all pancreatic endocrine cells [5, 6], Sox11 mediates the epithelial-to-mesenchymal transition process [7], allowing Ngn3-expressing pancreatic progenitors to migrate from the ductal epithelium to form α- and β-cell-containing pancreatic islets. Now, Khurana and Al-Hasani et al. demonstrate that DNA methylation represents a significant barrier in pancreatic β-cell regeneration in adulthood through their studies of pancreatic α-cell to β-cell-conversion in transgenic mouse models in a study that suggests targeting DNA methylation as a possible treatment for diabetes [4].

After three months of induction of pancreatic α-cell- to β-cell conversion, the authors discovered that the potent reactivation of both Ngn3 and Sox11 expression occurred alongside a significant reduction in promoter DNA methylation, as evidenced by methyl-domain-binding capture and downstream qPCR (MBD-qPCR) [8]. Interestingly, the study linked the transcriptional changes and the decrease in DNA methylation to the increased expression of the ten-eleven translocation (TET) family that catalyzes the stepwise oxidation of 5-methylcytosine in DNA to 5-hydroxymethylcytosine and further oxidation products resulting in the loss of methylation [9]. Specifically, Arx deletion induced DNA demethylation by upregulating Tet1 and Tet2 expression, while Pax4 overexpression induced DNA demethylation by upregulating Tet2 and Tet3 expression.

The authors next hope to explore the specific epigenetic mechanisms regulating Ngn3 expression in a regenerative context to develop a means to efficiently regenerate pancreatic β-cells in adulthood as a treatment for diabetes.

For more on how modulating DNA methylation may lead to an exciting treatment for diabetes, stay tuned to the Stem Cells Portal!


References

  1. Collombat P, Hecksher-Sørensen J, Broccoli V, et al., The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the α- and β-cell lineages in the mouse endocrine pancreas. Development 2005;132:2969.
  2. Al-Hasani K, Pfeifer A, Courtney M, et al., Adult Duct-Lining Cells Can Reprogram into β-like Cells Able to Counter Repeated Cycles of Toxin-Induced Diabetes. Developmental Cell 2013;26:86-100.
  3. Courtney M, Gjernes E, Druelle N, et al., The Inactivation of Arx in Pancreatic α-Cells Triggers Their Neogenesis and Conversion into Functional β-Like Cells. PLOS Genetics 2013;9:e1003934.
  4. Khurana I, Al-Hasani K, Maxwell S, et al., DNA methylation status correlates with adult β-cell regeneration capacity. npj Regenerative Medicine 2021;6:7.
  5. Gu G, Dubauskaite J, and Melton DA, Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 2002;129:2447.
  6. Schwitzgebel VM, Scheel DW, Conners JR, et al., Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 2000;127:3533.
  7. Xu X, D'Hoker J, Stangé G, et al., β Cells Can Be Generated from Endogenous Progenitors in Injured Adult Mouse Pancreas. Cell 2008;132:197-207.
  8. Pirola L, Balcerczyk A, Tothill RW, et al., Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Research 2011;21:1601-1615.
  9. Rasmussen KD and Helin K, Role of TET enzymes in DNA methylation, development, and cancer. Genes & Development 2016;30:733-750.