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

Diabetes. 2020 Nov;69(11):2490-2502. doi: 10.2337/db20-0382. Epub 2020 Aug 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Chromatin / metabolism
  • DNA Methylation
  • Diabetes Mellitus, Type 2 / metabolism*
  • Epigenesis, Genetic*
  • Epithelial Cells
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Humans
  • Kidney / cytology*
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism*
  • Transcriptome
  • Transforming Growth Factor beta1 / pharmacology


  • Chromatin
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • Transforming Growth Factor beta1

Associated data

  • figshare/10.2337/figshare.12749288