| First Author | Parveen N | Year | 2023 |
| Journal | Diabetes | Volume | 72 |
| Issue | 5 | Pages | 575-589 |
| PubMed ID | 36607262 | Mgi Jnum | J:335234 |
| Mgi Id | MGI:7468565 | Doi | 10.2337/db22-0506 |
| Citation | Parveen N, et al. (2023) DNA methylation Dependent Restriction of Tyrosine Hydroxylase Contributes to Pancreatic beta-cell Heterogeneity. Diabetes 72(5):575-89 |
| abstractText | The molecular and functional heterogeneity of pancreatic beta-cells is well recognized, but the underlying mechanisms remain unclear. Pancreatic islets harbor a subset of beta-cells that co-express Tyrosine Hydroxylase (TH), an enzyme involved in synthesis of catecholamines that repress insulin secretion. Restriction of the TH+ beta-cells within islets is essential for appropriate function in mice, such that higher proportion of these cells corresponds to reduced insulin secretion. Here, we use these cells as a model to dissect the developmental control of beta-cell heterogeneity. We define the specific molecular and metabolic characteristics of TH+ beta-cells, and show differences in their developmental restriction in mice and humans. We show that TH expression in beta-cells is restricted by DNA methylation during beta-cell differentiation. Ablation of de novo DNA methyltransferase Dnmt3a in the embryonic progenitors results in a dramatic increase in the proportion of TH+ beta-cells, while beta-cell specific ablation of Dnmt3a does not. We demonstrate that maintenance of Th promoter methylation is essential for its continued restriction in postnatal beta-cells. Loss of Th promoter methylation in response to chronic overnutrition increases the number of TH+ beta-cells, corresponding to impaired beta-cell function. These results reveal a regulatory role of DNA methylation in determining beta-cell heterogeneity. |
