Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity

Cell Metab. 2024 Jan 2;36(1):90-102.e7. doi: 10.1016/j.cmet.2023.11.018.

Abstract

Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity and function within multicellular tissues through incompletely known mechanisms. By assembling a single-cell atlas of chromatin state within human islets, we identified β cell subtypes governed by either high or low activity of the lineage-determining factor pancreatic duodenal homeobox-1 (PDX1). β cells with reduced PDX1 activity displayed increased chromatin accessibility at latent nuclear factor κB (NF-κB) enhancers. Pdx1 hypomorphic mice exhibited de-repression of NF-κB and impaired glucose tolerance at night. Three-dimensional analyses in tandem with chromatin immunoprecipitation (ChIP) sequencing revealed that PDX1 silences NF-κB at circadian and inflammatory enhancers through long-range chromatin contacts involving SIN3A. Conversely, Bmal1 ablation in β cells disrupted genome-wide PDX1 and NF-κB DNA binding. Finally, antagonizing the interleukin (IL)-1β receptor, an NF-κB target, improved insulin secretion in Pdx1 hypomorphic islets. Our studies reveal functional subtypes of single β cells defined by a gradient in PDX1 activity and identify NF-κB as a target for insulinotropic therapy.

Keywords: IL-1β; NF-κB; PDX1; chromatin; circadian; diabetes; inflammation; insulin; p65; β cells.

MeSH terms

  • Animals
  • Chromatin / metabolism
  • Genes, Homeobox
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Insulin-Secreting Cells* / metabolism
  • Mice
  • NF-kappa B* / metabolism

Substances

  • Chromatin
  • Homeodomain Proteins
  • NF-kappa B
  • pancreatic and duodenal homeobox 1 protein