Abstract: TH-PO0120
A Functional Promoter Connectivity Map of Human Kidney Cortex
Session Information
- Integrative Genomics and Multi-Omics in Noncystic Genetic Kidney Disease
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Schoberth, Mona, Universitatsklinikum Freiburg, Freiburg, BW, Germany
- Haddad, Safa, Albert-Ludwigs-Universitat Freiburg Institut fur Experimentelle und Klinische Pharmakologie und Toxikologie, Freiburg, BW, Germany
- Preissl, Sebastian, Universitat Graz, Graz, Styria, Austria
- Kottgen, Anna, Universitatsklinikum Freiburg, Freiburg, BW, Germany
- Haug, Stefan, Universitatsklinikum Freiburg, Freiburg, BW, Germany
- Akilesh, Shreeram, University of Washington, Seattle, Washington, United States
Background
Kidney diseases are driven by tissue-specific regulatory programs; e.g., variants in the UMOD promoter alter uromodulin expression in the thick ascending limb, increasing CKD risk. GWAS have implicated hundreds of loci in kidney disease, yet ~90% of variants fall in non-coding regions and are thought to disrupt the function of tissue-specific regulatory DNA elements (e.g. enhancers). Linking these variants to their causal target genes requires promoter-regulatory connectivity maps – not yet reported for kidney tissue. We generated a kidney regulatory map integrating promoter capture Hi-C (pcHiC), Hi-C, ATAC-seq, and ChIP-seq from primary human kidney tissue with deep learning-based sequence interpretation.
Methods
ATAC-seq was performed on kidney cortex (n=3), aligned to hg38 with peak calling (MACS2). Hi-C was performed on cortex and medulla from two donors. pcHiC was performed on cortex from two donors targeting 24,302 promoter regions (Arima protocol). ChIP-seq (H3K4me1, H3K4me3, H3K27ac) classified active and poised regulatory elements. ChromBPNet models trained on ATAC-seq were used to identify transcription factor binding motifs and their genome-wide positions.
Results
pcHiC identified >47,435 loops in both samples with a median loop size of ~200kb. 83.6-84.1% of pcHiC loops were encompassed within topology associated domains (TADs) which compartmentalize gene expression. ChIP-seq integration confirmed that 82.7–90.3% of promoter baits carried histone modifications typical of active promoters. ATAC-seq overlap showed 82–87% accessibility at both anchors, consistent with functional regulatory capture. Epigenetic classification revealed ~50% promoter-promoter, ~10% promoter-enhancer, and ~30% promoter-other loops. Promoter-promoter loops overwhelmingly involved kidney-expressed genes (93.7–96.6%), with >60% expressed at both anchors. ChromBPNet identified TEAD, HNF1B, NFIC, and AP-1 motifs were enriched at enhancers, while SP1 and NRF1 were restricted to promoters.
Conclusion
We present the first pcHiC maps from primary human kidney, revealing promoter-promoter and promoter-enhancer connectivity that is enriched for kidney-expressed genes. This resource enables linking non-coding GWAS variants to target genes through tissue-specific regulatory circuits. Cell-type-resolved integration using single-cell multiome data is ongoing and will be presented at ASN.