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| Status |
Public on Apr 03, 2023 |
| Title |
NF-kB and Circadian Enhancers Link β-cell Function with Anti-IL1B Therapy [ChIP/HiChIP-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Crosstalk between lineage-determining and signal-dependent transcription factors controls chromatin plasticity within heterogeneous tissues, yet how alterations in these interactions within single cells contribute to disease remains unknown. Here, by profiling chromatin activity in single nuclei of human pancreatic islets, we identified 19 clusters of cells, including β-cell subpopulations defined by differences in accessibility at non-coding cis-regulatory elements (CREs) for the lineage-determining factor pancreatic duodenal homeobox factor 1 (PDX1). Single cells with a high density of PDX1 CREs were enriched in accessible enhancer landscapes driving gene networks controlling nutrient sensing, insulin exocytosis, and circadian rhythms. In contrast, cells with reduced opening at PDX1 CREs had increased accessibility at regulatory elements for pro-inflammatory genes controlled by NF-kB and IL-1β. Genetic deficiency of Pdx1 in mice led to increased chromatin occupancy by the classical NF-κB subunit p65 and glucose intolerance that was more pronounced at the time of day when mice were awake and feeding. Within murine and human islets, PDX1 formed long-range repressive contacts with canonical regions of p65-mediated transcription. Pharmacological inhibition of signaling through the IL-1β receptor, an abundant β-cell target of p65, enhanced glucose-dependent insulin secretion in Pdx1-deficient β cells. Together, our single-cell epigenomic analyses provide a rationale to antagonize NF-kB signaling as an insulinotropic therapy for β-cell failure and diabetes.
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| Overall design |
Single-cell ATAC-sequencing, RNA-sequencing, ChIP-sequencing, HiChIP-sequencing, gene manipulation, metabolic studies
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| Contributor(s) |
Weidemann BJ |
| Citation(s) |
38171340 |
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| Submission date |
Oct 03, 2022 |
| Last update date |
Jan 31, 2024 |
| Contact name |
Benjamin J Weidemann |
| E-mail(s) |
[email protected]
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| Phone |
3127920532
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| Organization name |
NORTHWESTERN UNIVERSITY
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| Department |
Medicine
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| Lab |
Joseph Bass
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| Street address |
303 E. Superior St.
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60613 |
| Country |
USA |
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| Platforms (2) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL30172 |
NextSeq 2000 (Mus musculus) |
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| Samples (14)
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| This SubSeries is part of SuperSeries: |
| GSE214678 |
NF-kB and Circadian Enhancers Link β-cell Function with Anti-IL1B Therapy. |
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| Relations |
| BioProject |
PRJNA886680 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE214674_RAW.tar |
4.7 Gb |
(http)(custom) |
TAR (of BW, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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