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

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.

Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies

“…Systemic hypertension occurs frequently in diabetics and worsens intraglomerular hypertension and kidney microvascular damage. Bulk transcriptomic studies have been informative in both experimental models and human DKD (Bansal et al, 2020;Fan et al, 2019;Komers et al, 2014;Woroniecka et al, 2011). These studies have revealed important insights but are also limited because signals from minority cell types are lost in the integrated dataset.…”

Epigenetic Mechanisms in Diabetic Vascular Complications and Metabolic Memory: The 2020 Edwin Bierman Award Lecture

“…This was supported by in vivo findings in diabetic mice prone to atherosclerosis ( 40 ), suggesting that SET7 could be a useful therapeutic target. Recently, we performed multiomics analyses of renal tubular cells from subjects with T2D versus control subjects, which revealed epigenetic memory of dysregulation of several key genes associated with DKD and renal function ( 41 ).…”

Epigenetics and Inflammation in Diabetic Nephropathy

“…Roles of epigenetic modifications are not fully elucidated. Recently, single nucleus ATCT-seq integrated with snRNA-seq has been used to detect the cell-type-specific chromatin accessibility which enable to deep understanding of cell heterogeneity in kidney ( Bansal et al, 2020 ; Muto et al, 2021 ). It may provide a new approach to understand the epigentic modifications in DN.…”