| First Author | Weidemann BJ | Year | 2024 |
| Journal | Cell Metab | Volume | 36 |
| Issue | 1 | Pages | 90-102.e7 |
| PubMed ID | 38171340 | Mgi Jnum | J:388984 |
| Mgi Id | MGI:7574012 | Doi | 10.1016/j.cmet.2023.11.018 |
| Citation | Weidemann BJ, et al. (2024) Repression of latent NF-kappaB enhancers by PDX1 regulates beta cell functional heterogeneity. Cell Metab 36(1):90-102.e7 |
| abstractText | 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 beta cell subtypes governed by either high or low activity of the lineage-determining factor pancreatic duodenal homeobox-1 (PDX1). beta cells with reduced PDX1 activity displayed increased chromatin accessibility at latent nuclear factor kappaB (NF-kappaB) enhancers. Pdx1 hypomorphic mice exhibited de-repression of NF-kappaB and impaired glucose tolerance at night. Three-dimensional analyses in tandem with chromatin immunoprecipitation (ChIP) sequencing revealed that PDX1 silences NF-kappaB at circadian and inflammatory enhancers through long-range chromatin contacts involving SIN3A. Conversely, Bmal1 ablation in beta cells disrupted genome-wide PDX1 and NF-kappaB DNA binding. Finally, antagonizing the interleukin (IL)-1beta receptor, an NF-kappaB target, improved insulin secretion in Pdx1 hypomorphic islets. Our studies reveal functional subtypes of single beta cells defined by a gradient in PDX1 activity and identify NF-kappaB as a target for insulinotropic therapy. |
