Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1
Authors Komers R, Mar D, Denisenko O, Xu B, Oyama TT, Bomsztyk K
Submitted By Karol Bomsztyk on 10/29/2013
Status Published
Journal Laboratory investigation; a journal of technical methods and pathology
Year 2013
Date Published 5/1/2013
Volume : Pages 93 : 543 - 552
PubMed Reference 23508046
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 ?1 (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.

Investigators with authorship
Karol BomsztykUniversity of Washington