title: Histone H2AK119 and H2BK120 mono-ubiquitination modulate SET7/9 and SUV39H1 in type 1 diabetes-induced renal fibrosis.
abstract: Hyperglycaemia-induced expression of extracellular matrix (ECM) components plays a major role in the development of 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 monoubiquitination 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 was reduced. Changes in ubiquitin proteasome system components like increased Rnf2 (H2A-specific E3 ligase) and decreased H2A- and H2B-specific deubiquitinases (ubiquitin-specific proteases 7, 16, 21 and 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 also 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 and 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.
authors: Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
authors: Santosh Kumar
authors: SK
authors: Goru
authors: Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
authors: Almesh
authors: A
authors: Kadakol
authors: Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
authors: Anuradha
authors: A
authors: Pandey
authors: Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
authors: Vajir
authors: V
authors: Malek
authors: Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
authors: Nisha
authors: N
authors: Sharma
authors: Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
authors: Anil Bhanudas
authors: AB
authors: Gaikwad
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D054875:Ubiquitination / Q000502:physiology
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D006657:Histones; D003094:Collagen; D011495:Histone-Lysine N-Methyltransferase
keywords: H2AK119 mono-ubiquitination; H2BK120 mono-ubiquitination; histone H3 lysine dimeth; histone H3 lysine dimethylation; renal fibrosis; type 1 diabetes