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Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

Lookup NU author(s): Dr Andrew Advani

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Abstract

Histone protein modifications control fate determination during normal development and dedifferentiation during disease. Here, we set out to determine the extent to which dynamic changes to histones affect the differentiated phenotype of ordinarily quiescent adult glomerular podocytes. To do this, we examined the consequences of shifting the balance of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark in podocytes. Adriamycin nephrotoxicity and subtotal nephrectomy (SNx) studies indicated that deletion of the histone methylating enzyme EZH2 from podocytes decreased H3K27me3 levels and sensitized mice to glomerular disease. H3K27me3 was enriched at the promoter region of the Notch ligand Jag1 in podocytes, and derepression of Jag1 by EZH2 inhibition or knockdown facilitated podocyte dedifferentiation. Conversely, inhibition of the Jumonji C domain–containing demethylases Jmjd3 and UTX increased the H3K27me3 content of podocytes and attenuated glomerular disease in adriamycin nephrotoxicity, SNx, and diabetes. Podocytes in glomeruli from humans with focal segmental glomerulosclerosis or diabetic nephropathy exhibited diminished H3K27me3 and heightened UTX content. Analogous to human disease, inhibition of Jmjd3 and UTX abated nephropathy progression in mice with established glomerular injury and reduced H3K27me3 levels. Together, these findings indicate that ostensibly stable chromatin modifications can be dynamically regulated in quiescent cells and that epigenetic reprogramming can improve outcomes in glomerular disease by repressing the reactivation of developmental pathways.


Publication metadata

Author(s): Majumder S, Thieme K, Batchu SN, Alghamdi TA, Bowskill BB, Golam Kabir M, Liu Y, Advani SL, White KE, Geldenhuys L, Tennankore KK, Poyah P, Siddiqi FS, Advani A

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2018

Volume: 128

Issue: 1

Pages: 483-499

Print publication date: 02/01/2018

Acceptance date: 31/10/2017

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation

URL: https://doi.org/10.1172/JCI95946

DOI: 10.1172/JCI95946


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