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Genetics/Genomes/Proteomics/Metabolomics

Integrative Omics Analyses Reveal Epigenetic Memory in Diabetic Renal Cells Regulating Genes Associated With Kidney Dysfunction

  1. Anita Bansal1,
  2. Sreeram Balasubramanian2,
  3. Sangeeta Dhawan3,
  4. Amy Leung1,
  5. Zhen Chen1 and
  6. Rama Natarajan1⇑
  1. 1Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA
  2. 2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA
  3. 3Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA
  1. Corresponding author: Rama Natarajan, rnatarajan{at}coh.org
Diabetes 2020 Nov; 69(11): 2490-2502. https://doi.org/10.2337/db20-0382
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Abstract

Diabetic kidney disease (DKD) is a major complication of diabetes and the leading cause of end-stage renal failure. Epigenetics has been associated with metabolic memory in which prior periods of hyperglycemia enhance the future risk of developing DKD despite subsequent glycemic control. To understand the mechanistic role of such epigenetic memory in human DKD and to identify new therapeutic targets, we profiled gene expression, DNA methylation, and chromatin accessibility in kidney proximal tubule epithelial cells (PTECs) derived from subjects with and without type 2 diabetes (T2D). T2D-PTECs displayed persistent gene expression and epigenetic changes with and without transforming growth factor-β1 treatment, even after culturing in vitro under similar conditions as nondiabetic PTECs, signified by deregulation of fibrotic and transport-associated genes (TAGs). Motif analysis of differential DNA methylation and chromatin accessibility regions associated with genes differentially regulated in T2D revealed enrichment for SMAD3, HNF4A, and CTCF transcription factor binding sites. Furthermore, the downregulation of several TAGs in T2D (including CLDN10, CLDN14, CLDN16, SLC16A2, and SLC16A5) was associated with promoter hypermethylation, decreased chromatin accessibility, and reduced enrichment of HNF4A, histone H3-lysine-27-acetylation, and CTCF. Together, these integrative analyses reveal epigenetic memory underlying the deregulation of key target genes in T2D-PTECs that may contribute to sustained renal dysfunction in DKD.

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.12749288.

  • Received April 20, 2020.
  • Accepted July 30, 2020.
  • © 2020 by the American Diabetes Association
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Integrative Omics Analyses Reveal Epigenetic Memory in Diabetic Renal Cells Regulating Genes Associated With Kidney Dysfunction
Anita Bansal, Sreeram Balasubramanian, Sangeeta Dhawan, Amy Leung, Zhen Chen, Rama Natarajan
Diabetes Nov 2020, 69 (11) 2490-2502; DOI: 10.2337/db20-0382

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Integrative Omics Analyses Reveal Epigenetic Memory in Diabetic Renal Cells Regulating Genes Associated With Kidney Dysfunction
Anita Bansal, Sreeram Balasubramanian, Sangeeta Dhawan, Amy Leung, Zhen Chen, Rama Natarajan
Diabetes Nov 2020, 69 (11) 2490-2502; DOI: 10.2337/db20-0382
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