Abstract: FR-PO0375
FANCD2 Regulates the Transition from Adaptive to Maladaptive Repair in the Kidney Through Transcription Factor Coregulatory Networks
Session Information
- AKI: Mechanisms - Metabolism and Repair
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Konoe, Ran, Massachusetts General Hospital, Boston, Massachusetts, United States
- Inomata, Kenta, Keio Gijuku Daigaku, Minato, Tokyo, Japan
- Tekguc, Murat, Massachusetts General Hospital, Boston, Massachusetts, United States
- Mashouf, Parham, Massachusetts General Hospital, Boston, Massachusetts, United States
- Morizane, Ryuji, Massachusetts General Hospital, Boston, Massachusetts, United States
Group or Team Name
- Morozane lab
Background
Maladaptive repair after AKI drives CKD, yet how DNA repair proteins engage nuclear regulatory programs to preserve tubular repair fidelity remains unclear. Our human kidney and organoid analyses revealed distinct pan-nuclear and punctate redistribution of FANCD2, suggesting a noncanonical role beyond DNA repair.
Methods
We established an inducible FANCD2 knockdown (KD) model in human kidney organoids using a Lac operon-based shRNA system. LTL-positive proximal tubule volume was quantified by AI-assisted 3D volumetric analysis in separate differentiation and cisplatin-induced injury-recovery assays. FANCD2 ChIP-seq, de novo motif enrichment, and peak overlap analysis with publicly available transcription factor ChIP-seq datasets were used to identify FANCD2-associated chromatin regulatory networks. RNA-seq was integrated with FANCD2 ChIP-seq to determine whether genes linked to FANCD2-bound regulatory elements were transcriptionally altered by FANCD2 KD.
Results
FANCD2 KD significantly reduced LTL-positive proximal tubule volume during organoid differentiation, revealing an injury-independent role for FANCD2 in proximal tubule maturation. In an independent cisplatin-induced injury model, FANCD2-deficient organoids showed impaired recovery of proximal tubules, indicating increased injury vulnerability and defective tubular repair. FANCD2 ChIP-seq identified binding regions enriched for AP-2γ/AP-2α, ERRγ, Wnt/TCF pathway components (TCF7, LEF1), TCF21, and p63/HIC1/p53 motifs, implicating FANCD2-associated chromatin regions in developmental, nuclear receptor, and DNA damage/stress-response regulatory programs. Peak overlap analysis further showed strong overlap with RORγ binding sites, supporting a role as a nuclear receptor co-regulator.
Conclusion
These findings identify FANCD2 as a chromatin-level co-regulator that links DNA repair machinery to transcriptional programs governing tubular differentiation and injury recovery. Integrated organoid, ChIP-seq, and RNA-seq analyses support a model in which FANCD2 helps preserve repair fidelity through nuclear regulatory programs beyond canonical DNA repair. FANCD2 may represent a previously unrecognized molecular switch in the adaptive-to-maladaptive repair transition.
Funding
- NIDDK Support