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Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

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Majumder, Syamantak [1, 2, 3] ; Thieme, Karina [1, 2] ; Batchu, Sri N. [1, 2] ; Alghamdi, Tamadher A. [1, 2] ; Bowskill, Bridgit B. [1, 2] ; Kabir, M. Golam [1, 2] ; Liu, Youan [1, 2] ; Advani, Suzanne L. [1, 2] ; White, Kathryn E. [4] ; Geldenhuys, Laurette [5] ; Tennankore, Karthik K. [6] ; Poyah, Penelope [6] ; Siddiqi, Ferhan S. [6] ; Advani, Andrew [6]
Número total de Autores: 14
Afiliação do(s) autor(es):
[1] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON - Canada
[2] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON - Canada
[3] BITS, Dept Biol Sci, Pilani, Rajasthan - India
[4] Newcastle Univ, Electron Microscopy Res Serv, Newcastle Upon Tyne, Tyne & Wear - England
[5] Dalhousie Univ, Dept Pathol, Halifax, NS - Canada
[6] Dalhousie Univ, Dept Med, Halifax, NS - Canada
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: Journal of Clinical Investigation; v. 128, n. 1, p. 483-499, JAN 2 2018.
Citações Web of Science: 25

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. (AU)

Processo FAPESP: 16/04591-1 - RNAs não codificantes na doença renal diabética
Beneficiário:Karina Thieme
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado