I- What is the role of epigenetics in insulin gene expression and insulin secretion and action

Epigenetics literally refers to events that are above or beside genetics, that is, beyond DNA sequence alterations. In other words, an epigenetic phenomenon is a change in phenotype that is heritable, but does not involve DNA mutation. This change in phenotype must be switch-like and heritable even when the initial conditions that caused the switch disappear. The molecular view of epigenetics consists of the sum of alterations to DNA and histone proteins that collectively establish and propagate different patterns of gene expression and silencing from the same genome. Thus, DNA can be methylated and the histone tail can be subjected to many modifications such as acetylation, methylation, phosphorylation, ubiquitination, sumoylation, adenosine diphosphate (ADP) ribosylation, and proline isomerization, among others, all leading to alteration of the expression of the target gene (Figure 1).1 Whereas the role of DNA methylation in epigenetic regulation is well established, it remains to be seen whether all types of histone modifications contribute to the epigenetic state. Important environmental factors that have been demonstrated to modulate DNA methylation and histone modifications include nutrition, radiation, and chemical toxins.

1. Epigenetic control of insulin gene transcription

The human insulin (INS) gene is expressed exclusively in the β cells of the pancreatic islets and is clustered with three other genes in an interval of is of particular interest as these genes have been associated with obesity, birth size, type I diabetes, polycystic ovary syndrome, overgrowth in Beckwith–Wiedemann syndrome and possibly with hypertension.2 In addition, the INS gene was shown to physically interact with the synaptotagmin VIII (SYT8) gene located over 300 kb away, which encodes a transmembrane protein involved in the mediation of Ca2+ regulation of exocytosis
in β cells. This interaction is allowed by the binding of the CCCTCbinding factor (CTCF) to specific DNA sequence elements, called insulator sites (Figure 2).3 The role of such elements is to prevent inappropriate interactionsbetween adjacent chromatin domains and to organize the nearby genome: one type of insulator site establishes domains that separate enhancers and unrelated promoters in order to block their interaction, whereas a second type creates a barrier against the spread of silent heterochromatin. Interestingly, glucose timulates the INS-SYT8 interaction, which leads to increased SYT8 expression and thus coordinates insulin transcription and secretion (Gary Felsenfeld, Lecture).3

2. Metabolic programming of insulin secretion and action

Diet is one environmental factor that plays an important role in influencing the development and progression of T2D even early in life, and epigenetic regulation of gene expression has been implicated in mediating these programming effects of early diet. In the rat, exposure to maternal suboptimal nutrition (low protein, LP) during fetal and early postnatal life is a well-characterized model for nutritional programming of T2D. Indeed, the LP offspring undergo a loss of glucose tolerance and develop a phenotype similar to human T2D by 17 mo of age, ie, with the same age-dependent development of the phenotype as in humans. Moreover, LP offspring have alterations in the action of insulin and changes in the expression of proteins downstream of the insulin receptor in skeletal muscle (notably the phosphatidylinositol 3 [PI3] kinase/Akt pathway), as reported in young men with low birth weight characterized by increased future risk of insulin resistance and T2D.4 Using the LP model, Ozanne and colleagues studied the epigenetic regulation of the transcription factor hepatocyte nuclear factor 4-α (Hnf-4α) gene. This gene is the MODY (maturity-onset diabetes of the young) gene that has been the most extensively examined for association with common T2D and whose product is required for pancreatic β-cell differentiation and glucose homeostasis. They reported that maternal LP diet modified the interaction, at the Hnf4a locus, between the active P2 promoter and the enhancer region of the gene in pancreatic islets through alterations in histone marks. Precisely, LP islets were characterized by relative excess of the repressive mark H3K9me2 and loss of the active mark H3K4me1 at the enhancer region in both young and old rats, resulting in a permanent reduction in Hnf4a expression. In addition, maternal diet amplified the age-associated epigenetic silencing of this locus. Since pancreatic islets from T2D patients have reduced HNF4A expression of a magnitude similar to that observed in LP islets and common variants at the HNF4A locus show association with T2D, this suggests that the epigenetic mechanisms observed may contribute to the development of pancreatic β-cell dysfunction and the subsequent development of T2D in humans (Susan Ozanne, Lecture).5

3. Role of microRNA in insulin secretion and action

MicroRNAs (miRNAs) are small noncoding RNA molecules that function in most cases as translational repressors: they exert their action by partially pairing with one or more sequences in the 3’ untranslated region of target mRNAs. They are ubiquitously expressed, but some of them are restricted to a limited number of tissues where they are involved in many physiological and pathological processes such as tissue differentiation, cell proliferation, apoptosis, and inflammation. Numerous miRNAs are highly expressed during pancreatic islet development (such as miR-7, miR-9, miR-375, and miR-376, for example, in human) and were shown to be involved in the control of adult β-cell mass and function (such as miR-9, miR-124a, miR-29a, and miR-33a). Recently, Regazzi’s group identified new miRNAs (miR-21, miR-34a, and miR-146a) with an induced expression by proinflammatory cytokines in β cells and in islets of prediabetic NOD (nonobese diabetic) mice, suggesting that they may be involved in defective insulin secretion and apoptosis observed in diabetes.6 Interestingly, they also characterized miR-29a/b/c as an important actor in impairment of glucoseinduced insulin secretion (GIIS) and in β-cell apoptosis in type 1 diabetes (Romano Regazzi, Lecture).7

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The hyperstimulated β cell: prelude to diabetes?
I- What is the role of epigenetics in insulin gene expression and insulin secretion and action
II- Impact of insulin resistance on β-cell function
III- Intrinsic hyperstimulation of β-cells
IV- Modulation of β-cell function by secretory products
V- Conclusion
Lectures during IGIS meeting