Functional methylome analysis of human diabetic kidney disease.

Autor:	Park J; Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Guan Y; Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Sheng X; Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Gluck C; Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Seasock MJ; Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Hakimi AA; Department of Surgery, Urology Service, Memorial Sloan Kettering Medical Center, New York, New York, USA., Qiu C; Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Pullman J; Department of Pathology, Montefiore Medical Center, New York, New York, USA., Verma A; Department of Oncology and Developmental Biology, Albert Einstein College of Medicine, New York, New York, USA., Li H; Department of Epidemiology and Biostatistics and., Palmer M; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Susztak K; Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2019 Jun 06; Vol. 4 (11). Date of Electronic Publication: 2019 Jun 06 (Print Publication: 2019).
DOI:	10.1172/jci.insight.128886
Abstrakt:	In patients with diabetes mellitus, poor metabolic control has a long-lasting impact on kidney disease development. Epigenetic changes, including cytosine methylation, have been proposed as potential mediators of the long-lasting effect of adverse metabolic events. Our understanding of the presence and contribution of methylation changes to disease development is limited because of the lack of comprehensive base-resolution methylome information of human kidney tissue samples and site-specific methylation editing. Base resolution, whole-genome bisulfite sequencing methylome maps of human diabetic kidney disease (DKD) tubule samples, and associated gene expression measured by RNA sequencing highlighted widespread methylation changes in DKD. Pathway analysis highlighted coordinated (methylation and gene expression) changes in immune signaling, including tumor necrosis factor alpha (TNF). Changes in TNF methylation correlated with kidney function decline. dCas9-Tet1-based lowering of the cytosine methylation level of the TNF differentially methylated region resulted in an increase in the TNF transcript level, indicating that methylation of this locus plays an important role in controlling TNF expression. Increasing the TNF level in diabetic mice increased disease severity, such as albuminuria. In summary, our results indicate widespread methylation differences in DKD kidneys and highlights epigenetic changes in the TNF locus and its contribution to the development of nephropathy in patients with diabetes mellitus.
Databáze:	MEDLINE
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