Polycomb Repressive Complexes: Shaping Pancreatic Beta-Cell Destiny in Development and Metabolic Disease

Abstract

Pancreatic beta-cells secrete the hormone insulin, which is essential for the regulation of systemic glucose homeostasis. Insufficiency of insulin due to loss of functional beta-cells results in diabetes. Epigenetic mechanisms orchestrate the stage-specific transcriptional programs that guide the differentiation, functional maturation, growth, and adaptation of beta-cells in response to growth and metabolic signals throughout life. Primary among these mechanisms is regulation by the Polycomb Repressive Complexes (PRC) that direct gene-expression via histone modifications. PRC dependent histone modifications are pliable and provide a degree of epigenetic plasticity to cellular processes. Their modulation dictates the spatio-temporal control of gene-expression patterns underlying beta-cell homeostasis. Emerging evidence shows that dysregulation of PRC-dependent epigenetic control is also a hallmark of beta-cell failure in diabetes. This minireview focuses on the multifaceted contributions of PRC modules in the specification and maintenance of terminally differentiated beta-cell phenotype, as well as beta-cell growth and adaptation. We discuss the interaction of PRC regulation with different signaling pathways and mechanisms that control functional beta-cell mass. We also highlight recent advances in our understanding of the epigenetic regulation of beta-cell homeostasis through the lens of beta-cell pathologies, namely diabetes and insulinomas, and the translational relevance of these findings. Using high-resolution epigenetic profiling and epigenetic engineering, future work is likely to elucidate the PRC regulome in beta-cell adaptation versus failure in response to metabolic challenges and identify opportunities for therapeutic interventions.

Genome-wide association study and trans-ethnic meta-analysis identify novel susceptibility loci for type 2 diabetes mellitus

“…Studies have shown that the dysregulation of epigenetic mechanisms mediated by PRCs is a hallmark of β-cell failure in diabetes. Moreover, the dysregulation of PRC contributes to transcriptional changes associated with β-cell dysfunction in T2D [ 47 , 48 ]. These reports suggest that variants in these genes could impact T2D development and progression.…”

Senescence: a double-edged sword in beta-cell health and failure?

“…This is accompanied by an age-related increase in binding of the Trithorax complex containing Mll1 and JmjD3 which mark the chromatin with activating histone modifications, leading to p16 accumulation ( 44 ). The epigenetic control of p16 is driven by age-related changes in growth-factor signaling pathways ( 45 ). Platelet-derived Growth Factor (PDGF) signaling, which is essential for Ezh2 expression, declines with aging ( 46 ).…”

Beta cell dysfunction and dedifferentiation induced by Bone Morphogenetic Protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding

“…Histone modi cations have been shown to be involved in beta cell differentiation, identity, function and proliferation (35)(36)(37)(38). Moreover, evidence suggests that epigenetic mechanisms may be involved in the pathogenesis of diabetes (38)(39)(40)(41). Polycomb dependent histone methylation events have been implicated in beta cell dedifferentiation in both mouse and human beta cell dysfunction resulting in increased expression of genes associated with immature beta cell phenotype and a decrease in expression of genes associated with mature beta cells (38).…”