Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease
View abstract on PubMed
Summary
This summary is machine-generated.Dynamic histone modifications in kidney podocytes influence disease. Inhibiting specific enzymes that remove H3K27me3 marks can protect against glomerular diseases, suggesting epigenetic reprogramming as a therapeutic strategy.
Area Of Science
- Nephrology
- Epigenetics
- Molecular Biology
Background
- Histone modifications regulate cell fate during development and disease.
- Quiescent adult glomerular podocytes' differentiated state is influenced by dynamic histone changes.
- Histone H3 lysine 27 trimethylation (H3K27me3) is a key repressive mark.
Purpose Of The Study
- To investigate the role of dynamic histone modifications, specifically H3K27me3, in maintaining the differentiated phenotype of adult glomerular podocytes.
- To determine if manipulating H3K27me3 levels affects podocyte dedifferentiation and glomerular disease progression.
Main Methods
- Examined the effects of altering H3K27me3 balance in podocytes using genetic manipulation (EZH2 deletion) and pharmacological inhibitors (Jmjd3, UTX inhibitors).
- Utilized mouse models of glomerular disease, including adriamycin nephrotoxicity, subtotal nephrectomy (SNx), and diabetes.
- Analyzed H3K27me3 levels and gene expression (Jag1) in podocytes from diseased mice and human kidney biopsies.
Main Results
- Deletion of EZH2 (H3K27me3 methyltransferase) in podocytes reduced H3K27me3, sensitized mice to glomerular disease, and promoted podocyte dedifferentiation via Jag1 derepression.
- Inhibition of Jmjd3 and UTX (H3K27me3 demethylases) increased H3K27me3, attenuated glomerular disease in multiple models, and reduced Jag1 expression.
- Human patients with focal segmental glomerulosclerosis and diabetic nephropathy showed decreased podocyte H3K27me3 and increased UTX levels.
Conclusions
- Dynamic regulation of histone modifications like H3K27me3 occurs even in quiescent cells.
- Epigenetic reprogramming by inhibiting H3K27me3 demethylases shows therapeutic potential for glomerular diseases.
- Targeting epigenetic mechanisms can prevent podocyte dedifferentiation and disease progression by repressing developmental pathways.