Abstract: SA-PO0031
Hdac1/2 and Ezh2 Cooperate to Preserve Nephrogenesis by Restraining β-Catenin Signaling
Session Information
- Development, Stem Cells, and Regenerative Medicine
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 700 Development, Stem Cells, and Regenerative Medicine
Authors
- Liu, Hongbing, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Sohail, Muhammad Imran, Tulane University School of Medicine, New Orleans, Louisiana, United States
- El-Dahr, Samir S., Tulane University School of Medicine, New Orleans, Louisiana, United States
- Chen, Chaohui, Tulane University School of Medicine, New Orleans, Louisiana, United States
Background
Nephron progenitor maintenance and differentiation require precise coordination between developmental signaling pathways and epigenetic regulators. Histone deacetylases 1 and 2 (Hdac1/2) and the Polycomb repressive complex 2 methyltransferase Ezh2 are critical chromatin regulators of nephron progenitor cell (NPC) identity and fate. However, their cooperative roles in nephrogenesis remain poorly understood. We hypothesized that Hdac1/2 and Ezh2 coordinately control NPC fate by restraining Wnt/β-catenin signaling.
Methods
The compound knockout of Hdac1/2 and Ezh2 in NPCs were generated via sequential removal of Hdac1 and/or Hdac2 allele(s) from Ezh2 conditional knockout mice using Six2-Cre–mediated recombination. These mutant mice are designated 5-alleles mutants. Renal morphology and nephrogenesis were evaluated by histology, section immunofluorescence, and RNAscope.
Results
NPC-specific compound loss of three Hdac1/2 alleles together with biallelic Ezh2 deletion (5 allele mutants) resulted in severe nephrogenic defects characterized by reduced nephron endowment, tubular cyst formation, and disrupted nephron patterning. 5-allele mutant kidneys exhibited increased protein levels of active β-catenin and elevated expression of the Wnt targets such as Lef1 and Wnt4, indicating sustained activation of Wnt/β-catenin signaling. Mechanistically, mutant NPCs and nascent nephrons exhibited loss of the repressive histone markers H3K27me2/3, with a reciprocal and significant increase in H3K27ac, consistent with reduced Hdac1/2 and Ezh2 activity. Furthermore, we observed increased acetylation of β-catenin at Lys49, a modification known to promote its activation. In addition, 5-allele mutant NPCs demonstrated ectopic induction of Six1, an early nephrogenic transcription factor normally extinguished during nephron progenitor differentiation.
Conclusion
Hdac1/2 and Ezh2 cooperate to preserve nephrogenesis by restraining β-catenin signaling through both epigenetic and non-epigenetic mechanisms and maintaining transcriptional programs necessary for nephron progenitor differentiation and maturation. Sustained Six1 expression suggests developmental arrest and prolonged maintenance of an immature progenitor state. These findings provide new mechanistic insight into kidney development and establish Hdac1/2–Ezh2 cooperation as a critical safeguard of nephrogenesis.
Acknowledgment
Louisiana Board of Regents Support Fund LEQSF-RD-A-18