These GEITP pages have often discussed the fact that complex diseases almost always represent multifactorial phenotypes (traits) — (e.g. hypertension, schizophrenia, mental depressive disorder, cancer, autoimmunity, obesity, and diabetes) — which reflect contributions from genetics (alterations in DNA sequence), epigenetic factors (chromosomal events other than DNA variants), environmental effects (diet, lifestyle, smoking, prescription drugs, occupational hazards), endogenous influences (heart, kidney or lung disease), and our constantly changing microbiome (bacteria living in our intestine and in every orifice). Epigenetics is classically divided into: DNA methylation, RNA-interference (silencing miRNAs), histone modifications, and chromatin remodeling. The first two are so well understood that we now have commercially available assays to test for these, even genome-wide. The latter two processes are more elusive and are still under intense investigation.
The topic [of the attached article] is type-2 diabetes (T2D), commonly associated with obesity, inflammation, and insulin resistance. Insulin is produced in the beta-cells of the pancreas. Ultimately, diabetes results from insufficient numbers of insulin-secreting beta-cells — caused by impaired function, increased cell death, and/or loss of cell identity. Beta-cells are now known to be highly adaptable, and pioneering studies over the last decade have discovered networks of transcriptional and chromatin regulators that drive the development of beta-cell lineage. These networks provide barriers against trans-differentiation (i.e. loss of beta-cell identity). How these transcriptional programs remain stable over their long cellular lifespans seen (in the intact human or mouse pancreas) is not well understood. Important studies, both in wild-type and in genetic models, have pointed out that loss of beta cell identity (i.e. ‘dedifferentiation’ or ‘trans-differentiation’) is associated with increased metabolic stress (which is commonly seen with obesity and inflammation).
Authors [see attached article] combined deep epigenome-wide mapping analysis with single-cell transcriptomics to search for evidence of chromatin dysregulation in T2D. They found two chromatin-state “signatures” that are well correlated with beta-cell dysfunction — both in mice and in humans) — [a] ectopic activation of bivalent Polycomb-silenced domains, and [b] loss of expression at an epigenomically unique class of lineage-defining genes. Authors determined that beta-cell-specific loss-of-function of the Polycomb group repressive complex-2 (PRC2) gene expression in mice triggers diabetes-mimicking transcriptional chromatin-state signatures — combined with highly penetrant (in medical genetics, the proportion of those individuals carrying the mutant allele — who actually exhibit clinical symptoms) hyperglycemia (high blood sugar)-independent dedifferentiation. [Polycomb group (PcG) proteins are epigenetic regulators of transcription — essential for stem-cell identity, differentiation, and disease states — functioning within multiprotein complexes, called polycomb-repressive complexes (PRCs); PRCs modify histones (and other proteins) and silence target genes.] These intriguing data indicate that PRC2 dysregulation contributes to the complex disease T2D.
These breakthrough experiments provide a new direction for exploring beta-cell transcriptional regulation and identify PRC2 as a necessary polycomb-repressive complex for long-term maintenance of beta-cell identity. It’s a great example of genetics plus epigenetics contributing to a complex disease. Most fundamentally — this study suggests a “two-hit model” (i.e. chromatin, plus hyperglycemia) for explaining the loss of beta-cell identity in diabetes [and these data likely apply to both the autoimmune type-1 diabetes, as well as type-2 diabetes]. 😊
Cell Metabolism 5 June 2o19; 27 : 1294-1308