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.

Keywords: beta cells; diabetes; differentiation; epigenetics; maturation; polycomb; proliferation.

FIGURE 1

Polycomb control of beta cell differentiation and expansion (A) Polycomb proteins regulate the differentiation of pancreatic beta cells via sequential H3K27me3 patterning of stage-specific transcriptional programs. Polycomb eviction and consequent removal of H3K27me3 in response to developmental signals is essential for the activation of stage-specific transcription factors during definitive endoderm (DE) specification, marked by the presence of H3K4me3. The transition to pancreatic progenitors (PP) is coupled with the PcG dependent repression of DE genes, marked by gain of H3K27me3 and loss of H3K4me3. DE induction is also hallmarked by the creation of transcriptionally-poised chromatin state at gene promoters of pancreas specification, characterized by the presence of both H3K27me3 and H3K4me3. This regulatory process is reiterated during the subsequent stages of beta cell differentiation, such as PP to endocrine progenitors (EP) and EP to beta cells. Finally, PcG mediated repression of disallowed genes supports the functional maturation of beta cells. Key gene signatures of each developmental stage are noted in parentheses. (B) PcG mediated repression of the Ink4a/Arf locus is critical for the postnatal beta cell expansion and adaptive response. Age dependent down-regulation of PcG proteins combined with increased TrxG occupancy leads to induction of Ink4a/Arf expression and beta cell senescence. Age related changes in the actvitity of growth factor signaling pathways, namely PDGF and TGF-beta, play a key role in the PcG dependent control of beta cell homeostasis.