Hyperglycaemia-induced expression of extracellular matrix (ECM) components plays a major role in the development diabetic nephropathy (DN). The epigenetic mechanisms that modulate ECM gene expression in DN remain unclear. Therefore, we examined the role of histone H2A and H2B mono-ubiquitination on epigenetic chromatin marks such as histone H3 lysine dimethylation (H3K4Me2, H3K9Me2 and H3K79Me2) in type 1 diabetic rat kidney. Hyperglycaemia increased collagen deposition and Col1a1 gene expression. In whole kidney of diabetic animals, both H2AK119 mono-ubiquitination (H2AK119Ub) and H2BK120 mono-ubiquitination (H2BK120Ub) were found to be increased whereas, in glomeruli of diabetic animals expression of both H2AK119Ub and H2BK120Ub were reduced. Changes in ubiquitin proteasome (UPS) components like increased Rnf2 (H2A specific E3 ligase) and decreased H2A and H2B specific deubiquitinases (DUBs) (ubiquitin specific protease (USP) 7, 16, 21, 22) were also observed. Globally increased levels of chromatin marks associated with active genes (H3K4Me2 and H3K79Me2), and decreased levels of repressive marks (H3K9Me2) were observed. Hyperglycaemia also increased the protein expression of SET7/9 and decreased the expression of SUV39H1. We also showed the decreased occupancy of H2AK119Ub and H2BK120Ub on the promoters of Set7/9 and Suv39h1 in diabetic kidney. In addition, methylation marks regulated by H2AK119Ub (H3K27Me2, H3K36Me2) and H2BK120Ub (H3K4Me2 and H3K79Me2) were also found to be altered on the promoters of Set7/9 and Suv39h1 . Taken together, these results show the functional role of H2AK119Ub and H2BK120Ub in regulating histone H3K4Me2 and H3K9Me2 through modulating the expression of SET7/9 and SUV39H1 in the development of diabetic renal fibrosis.
- Type 1 diabetes
- H2AK119 mono-ubiquitination
- H2BK120 mono-ubiquitination
- Histone H3 lysine dimeth
- Histone H3 lysine dimethylation
- Renal fibrosis
- ©2016 The Author(s)
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