Abstract
Pancreatic beta cells play a central role in regulating glucose homeostasis by secreting the hormone insulin. Failure of beta cells due to reduced function and mass and the resulting insulin insufficiency can drive the dysregulation of glycemic control, causing diabetes. Epigenetic regulation by DNA methylation is central to shaping the gene expression patterns that define the fully functional beta cell phenotype and regulate beta cell growth. Establishment of stage-specific DNA methylation guides beta cell differentiation during fetal development, while faithful restoration of these signatures during DNA replication ensures the maintenance of beta cell identity and function in postnatal life. Lineage-specific transcription factor networks interact with methylated DNA at specific genomic regions to enhance the regulatory specificity and ensure the stability of gene expression patterns. Recent genome-wide DNA methylation profiling studies comparing islets from diabetic and non-diabetic human subjects demonstrate the perturbation of beta cell DNA methylation patterns, corresponding to the dysregulation of gene expression associated with mature beta cell state in diabetes. This article will discuss the molecular underpinnings of shaping the islet DNA methylation landscape, its mechanistic role in the specification and maintenance of the functional beta cell phenotype, and its dysregulation in diabetes. We will also review recent advances in utilizing beta cell specific DNA methylation patterns for the development of biomarkers for diabetes, and targeting DNA methylation to develop translational approaches for supplementing the functional beta cell mass deficit in diabetes.
Highlights
All of the distinct cell types in a multicellular organism share the same DNA sequence, and yet the phenotype of each individual cell type is unique, and dictated by the cell-type specific patterns of gene expression
Several studies have demonstrated that intrauterine growth restriction (IUGR) and maternal dietary variation alter the methylation patterns that govern the expression of transcription factors involved in beta cell identity and function, such as Hnf4a and Pdx1; leading to impaired functional beta cell mass and eventually diabetes [109, 133, 134]
Several studies have demonstrated that promoters of genes important for beta cell identity and function such as INS, PDX1, PPARGC1A and GLP1R are hypermethylated in human islets from donors with type 2 diabetes (T2D) compared to islets from non-diabetic donors [134, 155, 156, 158], resulting in their decreased expression and the consequent impairment of beta cell identity and insulin secretion
Summary
All of the distinct cell types in a multicellular organism share the same DNA sequence, and yet the phenotype of each individual cell type is unique, and dictated by the cell-type specific patterns of gene expression. Recent genome-wide DNA methylation profiling studies comparing islets from diabetic and non-diabetic human subjects demonstrate the perturbation of beta cell DNA methylation patterns, corresponding to the dysregulation of gene expression associated with mature beta cell state in diabetes.
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