Epigenetic modifications in metabolic memory: What are the memories, and can we erase them?

Abstract

Inherent and acquired abnormalities in gene regulation due to the influence of genetics and epigenetics (traits related to environment rather than genetic factors) underlie many diseases including diabetes. Diabetes could lead to multiple complications including retinopathy, nephropathy, and cardiovascular disease that greatly increase morbidity and mortality. Epigenetic changes have also been linked to diabetes-related complications. Genes associated with many pathophysiological features of these vascular complications (e.g., inflammation, fibrosis, and oxidative stress) can be regulated by epigenetic mechanisms involving histone posttranslational modifications, DNA methylation, changes in chromatin structure/remodeling, and noncoding RNAs. Intriguingly, these epigenetic changes triggered during early periods of hyperglycemic exposure and uncontrolled diabetes are not immediately corrected even after restoration of normoglycemia and metabolic balance. This latency in effect across time and conditions is associated with persistent development of complications in diabetes with prior history of poor glycemic control, termed as metabolic memory or legacy effect. Epigenetic modifications are generally reversible and provide a window of therapeutic opportunity to ameliorate cellular dysfunction and mitigate or "erase" metabolic memory. Notably, trained immunity and related epigenetic changes transmitted from hematopoietic stem cells to innate immune cells have also been implicated in metabolic memory. Hence, identification of epigenetic variations at candidate genes, or epigenetic signatures genome-wide by epigenome-wide association studies can aid in prompt diagnosis to prevent progression of complications and identification of much-needed new therapeutic targets. Herein, we provide a review of epigenetics and epigenomics in metabolic memory of diabetic complications covering the current basic research, clinical data, and translational implications.

Keywords: DNA methylation; diabetic complications; epigenetics; metabolic memory.

Graphical abstract

Figure 1.

Mediators of diabetic complications, involvement of epigenetic mechanisms and their persistence in metabolic memory. Hyperglycemia in diabetes or risk factors associated with diabetes such as obesity/insulin resistance, dyslipidemia, and hypertension alter the production or activity of multiple molecules including ROS, AGEs, oxidized LDL, and NO, activate signaling pathways such as the polyol, hexosamine, PKC, and NF-κB, and subsequently induce proinflammatory cytokines (e.g., TNF-α, IL1, and IL6), chemokines (e.g., CCL2), and various disease/cell-specific growth and fibrotic factors such as TGF-β1, AngII, IGF, VEGF, angiopoietins, collagens, and fibronectin. These diabetic stimuli, especially hyperglycemia, and the indicated subsequent downstream effects can also induce epigenetic changes including DNAme, histone PTMs, chromatin-remodeling, along with ncRNAs (lncRNAs and miRNAs) that can act via epigenetic mechanisms. Persistence of some of these changes even after glucose levels are normalized can cause long-term persistent cellular malfunction including mitochondrial dysfunction, oxidative stress, and ER stress. This results in prolonged pathological changes such as inflammation with monocyte/macrophage infiltration, fibrosis with extracellular matrix accumulation, hypertrophy, and cell death (apoptosis) in diabetes-targeted cells/tissues/organs, leading to development and/or uncontrolled progression of complications including retinopathy, DKD, neuropathy, and CVD, sometimes even after glycemic control. AGE, advanced glycation end product; AngII, angiotensin II; CCL2-C, C motif chemokine ligand 2; CVD, cardiovascular disease; DKD, diabetic kidney disease; DNAme, DNA methylation; ER, endoplasmic reticulum; histone PTM, histone posttranslational modification; IGF, insulin-like growth factor; IL1, interleukin 1; IL6-interleukin 6; LDL, low density lipoprotein; lncRNA, long noncoding RNA; miRNA, microRNAs; ncRNA, noncoding RNA; NF-κB, nuclear factor κB; NO, nitric oxide; PKC, protein kinase C; ROS, reactive oxygen species; TGF-β1, transforming growth factor β1; VEGF, vascular endothelial growth factor.

Figure 2.

Epigenetic regulation of gene expression. Key epigenetic marks, including DNAme and histone PTMs, associated with euchromatin and heterochromatin are shown in A and C, respectively, and the interconversions between these two chromatin structures are shown in B. DNAme and histone PTMs interface with chromatin remodeling complexes, and noncoding (nc) RNAs to remodel chromatin into two major chromatin states, euchromatin and heterochromatin. At euchromatin (A) where loosely packed nucleosomes allow open chromatin states more easily accessible to transcription factors and RNA polymerases, gene promoters are usually enriched with marks such as histone H3K4me3 and H3K9ac, enhancers with H3K4me1 and H3K27ac, and gene bodies with H3K36me3. DNAme levels are low at enhancers and promoters, and high in gene bodies. With the binding of transcription factors to enhancers and promoters in euchromatin, RNA polymerases are recruited to either coding or noncoding (including pri-miRNAs and lncRNAs) genes for active transcription. Pri-miRNAs are processed to mature miRNAs via posttranscriptional processes in the cytoplasm, and lncRNA can modulate chromatin functions by interaction with chromatin factors, RNA binding proteins, and enhancers (not shown). On the other hand, nucleosomes at heterochromatin (C) are densely packed and the associated epigenetic marks include H3K9me3, H3K27me3 and DNAme. With reduced accessibility to transcription factors and RNAs polymerases at heterochromatin regions, gene transcription/expression is inhibited. The signals of each epigenetic mark enriched at euchromatin or heterochromatin regions can be modified by the dynamic actions of writers or erases, including histone and DNA methyltransferases, histone acetyltransferases, demethylases, and deactylases (shown in B) allowing for the remodeling of chromatin structure. TSS, transcription start site; DNMT, DNA methyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase; KDM, histone lysine demethylase; KMT, histone lysine methyltransferase; PTMs, posttranslational modifications; TET, ten-eleven translocation enzyme.

Figure 3.

Metabolic memory and underlying epigenetic mechanisms. A: schematic diagram depicting the association between glycemic control and the phenomenon of metabolic memory as derived from in vitro studies and in vivo studies with animals and diabetic patients. Depicted are glucose levels in the blood or cell growth medium between two groups of diabetic patients (e.g., patients with T1D in DCCT study), diabetic animals or cultured cells from target organs over two time periods (different or similar glycemic control periods as shown on the X-axis). During the “different-glycemic control” period, one group consisted of diabetic patients or animals experiencing high blood glucose (HG, e.g., high HbA1c levels of patients in DCCT CONV group) due to poor glycemic control, or cells grown in medium containing HG. The other group consisted of diabetic patients (e.g., DCCT INT group) or animals or cells maintained at normal glucose (NG) levels. At the end of this period, the glycemic control of HG group was changed to be similar to that in the group with NG, such that the glucose levels of both groups were normal or close-to-normal (“similar-glycemic control” Period). B: schematic diagram depicting different rates of incidences of diabetic complication development/progression or levels of complication-associated molecular changes between the two groups of diabetic patients/animals/cells over the same two time periods. During “different-glycemic control” period, HG group showed higher incidence of cell/organ dysfunction and complication development or progression compared with NG group. During the “similar-glycemic control” period, despite maintaining the glucose in both groups at the same normal or close-to-normal levels, the former HG treatment group continue to have higher rates of cellular dysfunction and complication development compared with the former NG group. This phenomenon has been called metabolic memory. C: evidence for the involvement of epigenetic mechanisms in metabolic memory. During the “different-glycemic control” period, HG decreased DNAme and/or histone PTMs associated with heterochromatin (e.g., H3K9me3 and H3K27me3) and increased euchromatin-associated PTMs (e.g., H3K4me3, H3K9ac, and H3K4me1) at key genes (gene symbols of some examples are listed below each modification) relevant to pathophysiological changes (such as inflammation, oxidative stress, and mitochondrial dysfunction) associated with diabetic complications in target cells/tissues. These epigenetic changes upregulate the expression of the corresponding genes. On the other hand, HG could also increase DNAme or H4K20me3 (another mark for heterochromatin) and decrease euchromatin-associated marks (H3K4me1 and H3K27ac) at some other “protective” genes (symbols listed), which downregulated the expression of the corresponding genes. Importantly, these epigenetic changes established during the “Different-glycemic control” period can persist in the second “similar-glycemic control” period, leading to persistent gene expression changes, organ dysfunction, and sustained complications, highlighting epigenetic mechanisms for metabolic memory. Besides DNAme and histone PTMs, the expression of some mature miRNAs was modified by HG during the first period with changes persisting during the second period. The potential involvement of some lncRNAs in metabolic memory has also been suggested in some studies. CONV, conventional glycemic control group; DCCT, Diabetes Control and Complications Trial; INT, intensive glycemic control; PTMs, posttranslational modifications; T1D, type 1 diabetes.