ABSTRACT
To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track ß cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. ß cell-specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring ß cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of ß cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of ß cell identity in diabetes.
Subject(s)
Chromatin/metabolism , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat , Gene Silencing , Insulin-Secreting Cells/metabolism , Polycomb Repressive Complex 2/physiology , Animals , Cell Differentiation/genetics , Cells, Cultured , Chromosome Mapping , Diabetes Mellitus, Type 2/genetics , Epigenomics , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Humans , Hyperglycemia/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid-Lymphoid Leukemia Protein/genetics , Myeloid-Lymphoid Leukemia Protein/metabolism , Polycomb Repressive Complex 2/genetics , Single-Cell AnalysisABSTRACT
Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance. We demonstrate that in mice obesity promotes expansion of a distinct, interleukin-6 receptor (IL6R)a-expressing NK subpopulation, which also expresses a number of other myeloid lineage genes such as the colony-stimulating factor 1 receptor (Csf1r). Selective ablation of this Csf1r-expressing NK cell population prevents obesity and insulin resistance. Moreover, conditional inactivation of IL6Ra or Stat3 in NK cells limits obesity-associated formation of these myeloid signature NK cells, protecting from obesity, insulin resistance, and obesity-associated inflammation. Also in humans IL6Ra+ NK cells increase in obesity and correlate with markers of systemic low-grade inflammation, and their gene expression profile overlaps with characteristic gene sets of NK cells in obese mice. Collectively, we demonstrate that obesity-associated inflammation and metabolic disturbances depend on interleukin-6/Stat3-dependent formation of a distinct NK population, which may provide a target for the treatment of obesity, metaflammation-associated pathologies, and diabetes.