2. Academic Validation
  3. Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity

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.
Benjamin J Weidemann 1,  Biliana Marcheva 1,  Mikoto Kobayashi 1,  Chiaki Omura 1,  Marsha V Newman 1,  Yumiko Kobayashi 1,  Nathan J Waldeck 1,  Mark Perelis 2,  Louise Lantier 3,  Owen P McGuinness 3,  Kathryn Moynihan Ramsey 1,  Roland W Stein 4,  Joseph Bass 5
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 2 Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
  • 3 Vanderbilt-NIH Mouse Metabolic Phenotyping Center, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 4 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 5 Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: j-bass@northwestern.edu.
PMID: 38171340 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.

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