Update: the role of epigenetics in the metabolic memory of diabetic complications

Abstract

Diabetes, a chronic disease characterized by hyperglycemia, is associated with significantly accelerated complications, including diabetic kidney disease (DKD), which increases morbidity and mortality. Hyperglycemia and other diabetes-related environmental factors such as overnutrition, sedentary lifestyles, and hyperlipidemia can induce epigenetic changes. Working alone or with genetic factors, these epigenetic changes that occur without alterations in the underlying DNA sequence, can alter the expression of pathophysiological genes and impair functions of associated target cells/organs, leading to diabetic complications like DKD. Notably, some hyperglycemia-induced epigenetic changes persist in target cells/tissues even after glucose normalization, leading to sustained complications despite glycemic control, so-called metabolic memory. Emerging evidence from in vitro and in vivo animal models and clinical trials with subjects with diabetes identified clear associations between metabolic memory and epigenetic changes including DNA methylation, histone modifications, chromatin structure, and noncoding RNAs at key loci. Targeting such persistent epigenetic changes and/or molecules regulated by them can serve as valuable opportunities to attenuate, or erase metabolic memory, which is crucial to prevent complication progression. Here, we review these cell/tissue-specific epigenetic changes identified to-date as related to diabetic complications, especially DKD, and the current status on targeting epigenetics to tackle metabolic memory. We also discuss limitations in current studies, including the need for more (epi)genome-wide studies, integrative analysis using multiple epigenetic marks and Omics datasets, and mechanistic evaluation of metabolic memory. Considering the tremendous technological advances in epigenomics, genetics, sequencing, and availability of genomic datasets from clinical cohorts, this field is likely to see considerable progress in the upcoming years.

Keywords: diabetic complications; diabetic kidney disease; epigenetic modifications; epigenetics; metabolic memory.

Graphical abstract

Figure 1.

Schematic representation of key epigenetic alterations in chromatin histones and DNA. A: histone methylation refers to the addition of methyl groups (green or red circles labeled as Me) to histone tails at lysines and other amino acids at various locations and can be associated with gene activation or repression. Histone methylation can be introduced by histone methyltransferases (HMTs) such as H3K9-specific SUV39H1/2, H3K4-specific SET7/9, and enhancer zeste homolog 2 (EZH2) complex for H3K27me3. Histone demethylation can be catalyzed by histone lysine demethylases (KDMs) such as KDM1A and Jumanji C-domain-containing proteins (JMJDs). B: histone acetylation refers to the addition of acetyl groups (green circles labeled AC) to the various locations on histone tails. It is regulated by histone acetyltransferases [HATs, such as CREB binding protein (CBP/p300) and Gcn5-related N-acetyltransferases (GNAT)] and histone deacetylases [HDACs, such as HDACs1-11 and sirtuins (SIRT1-7)]. Histone acetylation is associated with active gene expression/transcription, whereas deacetylation is associated with gene repression. C: DNA methylation (DNAme) mainly refers to covalent addition of methyl groups (red circles labeled as Me) to cytosines at cytosine-phosphate-guanine dinucleotides (CpGs) to form 5-methylcytosine (5mC). DNAme can be catalyzed by methyltransferases (DNMTs) including DNMT3A, DNMT3B, and DNMT1 and reversed by the ten-eleven translocation proteins (TET1, TET2, and TET3). The functions of DNAme vary depending on its genomic location relative to genes. DNA methylation at promoter regions can repress gene expression and vice versa for DNA demethylation. Methyl donor groups used for DNAme and histone methylation can be provided by metabolic precursors S-adenosylmethionine (SAM) and acetyl groups for histone acetylation by acetyl-CoA. Green pointed arrows represent the activation of gene expression by the corresponding epigenetic changes, whereas the red blocked arrows refer to repression of gene expression. [Created with BioRender.com.]

Figure 2.

Epigenetic alterations and metabolic memory in the development of diabetic kidney disease (DKD). Hyperglycemia and other metabolic insults/abnormalities in diabetes induce changes in various factors in the target cells or tissues. These factors include advanced glycation end products (AGEs), oxidized low-density lipoprotein (OX-lipids), growth factors (GFs) such as transforming growth factor-β1 (TGF-β1) and connective tissue growth factor, reactive oxygen species (ROS), proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), and chemokines such as C-C motif chemokine ligand (CCL)-2, and hemodynamic factors such as angiotensin II. The target cells affected in DKD include tubular epithelial cells, glomerular mesangial cells, glomerular podocytes, vascular endothelial cells, vascular smooth muscle cells (VSMCs), or circulating inflammatory/immune cells especially monocytes that transform to macrophages when they infiltrate into the kidney. These dysregulated factors induce cellular dysfunctions including oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunctions. Persistent changes in DNA methylation, histone methylation, and acetylation at key genomic loci associated with DKD as well as sustained expression of pathological microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have been identified in in vitro and in vivo studies and in human clinical studies mimicking metabolic memory. These epigenetic changes/mechanisms maintain the sustained changes in the expression of various genes and factors, activation of signaling pathways and cellular dysfunction, leading to continued pathological changes including inflammation, apoptosis, hypertrophy, and fibrosis even after normalization of glucose levels. These pathological changes cause chronic renal dysfunction due to podocyte injury, vascular dysfunction, glomerular sclerosis, and tubulointerstitial fibrosis, ultimately resulting in persistent DKD development and progression. [Created with BioRender.com.]