The Polycomb-dependent epigenome controls β-cell dysfunction, dedifferentiation and diabetes

Abstract

SUMMARYChromatin is the physical template that stabilizes and specifies transcriptional programs. To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combined deep epigenome mapping with single cell transcriptomics to mine for evidence of chromatin dysregulation in type-2 diabetes. We identify two chromatin-state signatures that track the trajectory of β-cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-domains and a loss of expression at a subclass of highly active domains containing key lineage-defining genes. β-cell specific deletion of Polycomb (Eed/PRC2) triggers parallel transcriptional signatures. Intriguingly, these β-cell Eed-knockouts also exhibit highly penetrant hyperglycemia-independent dedifferentiation indicating that Polycomb dysregulation sensitizes the β-cell for dedifferentiation. These findings provide novel resources for exploring transcriptional and epigenetic control of β-cell (dys)function. They identify PRC2 as necessary for long-term maintenance of β-cell identity. The data suggest a two-hit model for loss of β-cell identity in diabetes and highlight epigenetic therapeutic potential to block dedifferentiation.

Beta-Cell Dedifferentiation in Type 2 Diabetes: Concise Review

“…The key role of epigenetic changes in altering the transcription factor profile in β cells in T2D has been demonstrated in a recent study on the effects of the polycomb complex PRC2 . PRC2‐mediated methylation of the histone lysine residue H3K27 serves to silence gene expression.…”

Advances in epigenetics link genetics to the environment and disease

“…Therefore, metabolic alterations can induce global perturbations of the epigenome and mutant metabolic components represent potential therapeutic targets 83,84 . On the other hand, metabolic changes can affect specific loci and induce long-lasting epigenetic modifications, including intergenerational epigenetic inheritance [85][86][87] . The effectors of these perturbations are DNA methylation, Polycomb components, and transfer RNA (tRNA) fragments, which, among other effects, repress genes associated with endogenous retroelements and might thereby help to preserve genome integrity [87][88][89] .…”

Islet Identity in Transplantation Procedures: The Intersection of Cellular Maturity and Function

“…Multiple mechanisms have been attributed, including oxidative stress from glucose metabolism [92,93], and endoplasmic reticulum (ER) strain, specifically the unfolded protein response (UPR), causing impaired insulin secretion [94][95][96]. Lu et al depicts β-cell loss of identity as the result of a two-hit hypothesis: sustained metabolic stress on the β-cell, and loss of polycomb-silencing via PRC2, triggering dedifferentiation of β-cells and consequent diabetes [97]. Polycomb comprises two repressive complexes, PRC1 and PRC2, which control gene silencing [98].…”