Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis.
Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. Hypermethylation of the Rasal1 promoter contributes to activation of fibroblasts and progression of kidney fibrosis. Here, we explored whether such causative hypermethylation could be reversed through endogenous mechanisms and whether such reversal of hypermethylation is a constituent of the antifibrotic activity of bone morphogenic protein 7 (BMP7). We show that successful inhibition of experimental kidney fibrosis through administration of BMP7 associates with normalization of Rasal1 promoter hypermethylation. Furthermore, this reversal of pathologic hypermethylation was achieved specifically through Tet3-mediated hydroxymethylation. Collectively, our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis.
Departments of Nephrology and Rheumatology, and.
Björn
B
Tampe
Departments of Nephrology and Rheumatology, and.
Desiree
D
Tampe
Departments of Nephrology and Rheumatology, and Department of Transplantation, Immunology and Immunohematology, Tübingen University Medical Center, Eberhard Karls University, Tübingen, Germany;
Claudia A
CA
Müller
Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas; and.
Hikaru
H
Sugimoto
Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas; and.
Valerie
V
LeBleu
Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), Göttingen, Germany.
Xingbo
X
Xu
Departments of Nephrology and Rheumatology, and.
Gerhard A
GA
Müller
Cardiology and Pneumology, Göttingen University Medical Center, Georg August University, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), Göttingen, Germany.
Elisabeth M
EM
Zeisberg
Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas; and rkalluri@mdanderson.org mzeisberg@med.uni-goettingen.de.
Raghu
R
Kalluri
Departments of Nephrology and Rheumatology, and rkalluri@mdanderson.org mzeisberg@med.uni-goettingen.de.
Michael
M
Zeisberg
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D020690:GTPase-Activating Proteins / Q000235:genetics*; D020868:Gene Silencing; D051379:Mice; D009400:Nephrosclerosis / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D014517:Ureteral Obstruction / Q000209:etiology / Q000235:genetics / Q000517:prevention & control
D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D011518:Proto-Oncogene Proteins; C000590956:RASAL1 protein, mouse; C525820:bmp7 protein, mouse; D049308:Dioxygenases; C551915:Tet3 protein, mouse