# Lysine-specific histone demethylase 1a regulates nephron development and long-term transcriptional programming

## TL;DR

This study shows that the enzyme LSD1 is essential for kidney development and its absence leads to kidney disease and cyst formation.

## Contribution

The study identifies LSD1's role in nephron development and its impact on long-term kidney function and cyst formation.

## Key findings

- Kdm1a depletion in nephron progenitor cells causes reduced kidney size and later kidney disease in mice.
- CRISPR/Cas9 deletion of KDM1A in human kidney organoids leads to cyst formation and altered gene expression.
- Noncoding RNAs are implicated in cell proliferation following Kdm1a deletion.

## Abstract

Low nephron endowment constitutes a risk factor for hypertension and renal disease. Epigenetic regulation is crucial for nephron progenitor cell differentiation, affecting nephron number and renal function. The role of many epigenetic modulators, such as Lysine-specific histone demethylase 1a (LSD1 or KDM1A), remains unclear. We used Kdm1a-KO mice to demonstrate that Kdm1a depletion in nephron progenitor cells results in reduced kidney size in neonates and led to glomerulosclerosis, proteinuria, and renal cysts in adults. Notably, Kdm1a deletion in podocytes or tubular cells did not replicate these effects. CRISPR/Cas9-mediated KDM1A deletion in human kidney organoids caused cyst formation and altered gene expression, with snRNA-seq revealing downregulation of podocyte genes and upregulation of metabolic genes. The presence of noncoding RNAs indicated roles in cell proliferation. Our study reveals the critical role of Kdm1a function in nephron development and highlights its affect on transcriptional programming for long-term renal function and susceptibility to cyst formation.

LSD1 regulates kidney development, and its dysfunction disrupts key kidney cells, leading to cyst formation. Targeting LSD1 could offer new treatments for kidney diseases.