Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1 diabetes

Radko Komers, Daniel Mar, Oleg Denisenko, Bei Xu, Terry T. Oyama, Karol Bomsztyk

Research output: Contribution to journalArticle

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Abstract

Epigenetic processes are increasingly being recognized as factors in the pathophysiology of diabetes complications, but few chromatin studies have been done in diabetic nephropathy (DN). We hypothesized that changes in mRNA expression of DN-related genes are associated with epigenetic alterations and aberrant expression of histone-modifying enzymes. RT-PCR and a matrix-chromatin immunoprecipitation platform were used to examine renal mRNA expression, RNA polymerase II (Pol II) recruitment, and epigenetic marks at DN-related genes in the mouse (OVE26) and streptozotocin-induced rat models of type 1 diabetes. Diabetes induced renal expression of Cox2, S100A4/FSP-1, and vimentin genes in both the mouse and the rat models of DN. Mcp-1 and laminin γ1 (Lamc1) expression were increased in diabetic mice but not in rats. Comparison of mRNA and Pol II levels suggested that the diabetes-induced expression of these transcripts is mediated by transcriptional and posttranscriptional processes. Decreases in histone H3 lysine 27 tri-methylation (H3K27m3, silencing mark) and increases in H3 lysine 4 di-methylation (H3K4m2, activating mark) levels were the most consistent epigenetic alterations in the tested genes. In agreement with these results, immunoblot analysis showed increased protein abundance of renal H3K27m2/3 demethylase KDM6A, but no changes in cognate methyltransferase Ezh2 in kidneys of the OVE26 mice compared with controls. In diabetic rats, Ezh2 expression was higher without changes in KDM6A, demonstrating that mechanisms of DN-induced H3K27m3 loss could be species specific. In summary, we show that altered mRNA expression of some DN-related genes is associated with changes in Pol II recruitment and a corresponding decrease in repressive H3K27m3 at the selected loci, and at least in mice with equivalent changes in renal expression of cognate histone-modifying enzymes. This pattern could contribute to diabetes-mediated transitions in chromatin that facilitate transcriptional changes in the diabetic kidney.

Original languageEnglish (US)
Pages (from-to)543-552
Number of pages10
JournalLaboratory Investigation
Volume93
Issue number5
DOIs
StatePublished - May 2013

Fingerprint

Diabetic Nephropathies
Type 1 Diabetes Mellitus
Epigenomics
Kidney
Histones
Genes
Messenger RNA
Methylation
Lysine
Chromatin
Genetic Epigenesis
RNA Polymerase II
Chromatin Immunoprecipitation
Methyltransferases
Vimentin
Diabetes Complications
Enzymes
Streptozocin
Polymerase Chain Reaction
Proteins

Keywords

  • diabetic nephropathy
  • histone enzymes
  • histone modifications
  • RNA polymerase II

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1 diabetes. / Komers, Radko; Mar, Daniel; Denisenko, Oleg; Xu, Bei; Oyama, Terry T.; Bomsztyk, Karol.

In: Laboratory Investigation, Vol. 93, No. 5, 05.2013, p. 543-552.

Research output: Contribution to journalArticle

Komers, R, Mar, D, Denisenko, O, Xu, B, Oyama, TT & Bomsztyk, K 2013, 'Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1 diabetes', Laboratory Investigation, vol. 93, no. 5, pp. 543-552. https://doi.org/10.1038/labinvest.2013.47
Komers, Radko ; Mar, Daniel ; Denisenko, Oleg ; Xu, Bei ; Oyama, Terry T. ; Bomsztyk, Karol. / Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1 diabetes. In: Laboratory Investigation. 2013 ; Vol. 93, No. 5. pp. 543-552.
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