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Epigenetics and epigenomics in diabetic kidney disease and metabolic memory

Nature Reviews Nephrology volume 15, pages 327–345 (2019)Cite this article

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Abstract

The development and progression of diabetic kidney disease (DKD), a highly prevalent complication of diabetes mellitus, are influenced by both genetic and environmental factors. DKD is an important contributor to the morbidity of patients with diabetes mellitus, indicating a clear need for an improved understanding of disease aetiology to inform the development of more efficacious treatments. DKD is characterized by an accumulation of extracellular matrix, hypertrophy and fibrosis in kidney glomerular and tubular cells. Increasing evidence shows that genes associated with these features of DKD are regulated not only by classical signalling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation and non-coding RNAs. These mechanisms can respond to changes in the environment and, importantly, might mediate the persistent long-term expression of DKD-related genes and phenotypes induced by prior glycaemic exposure despite subsequent glycaemic control, a phenomenon called metabolic memory. Detection of epigenetic events during the early stages of DKD could be valuable for timely diagnosis and prompt treatment to prevent progression to end-stage renal disease. Identification of epigenetic signatures of DKD via epigenome-wide association studies might also inform precision medicine approaches. Here, we highlight the emerging role of epigenetics and epigenomics in DKD and the translational potential of candidate epigenetic factors and non-coding RNAs as biomarkers and drug targets for DKD.

Key points

  • Diabetic kidney disease (DKD), involving the accumulation of extracellular matrix, hypertrophy and fibrosis in kidney glomerular and tubular cells, can lead to end-stage renal disease.

  • Genes associated with DKD are regulated not only by classical signalling pathways and transcription factors but also by epigenetic mechanisms, including chromatin histone modifications, DNA methylation and non-coding RNAs.

  • Metabolic memory is a phenomenon characterized by the persistent expression of DKD-related genes and phenotypes induced by glycaemic exposure despite subsequent glycaemic control.

  • Persistent epigenetic changes (DNA methylation and histone modifications) and signalling circuitry mediated by non-coding RNAs may be involved in metabolic memory.

  • Targeting epigenetic factors (using small molecules or locus-specific epigenetic editing via the CRISPR–Cas9 system) or non-coding RNAs (using chemically modified antisense oligonucleotides) are potential approaches to prevent or treat DKD and erase metabolic memory.

  • Epigenetic profiling through epigenome-wide association studies and RNA (transcriptome) profiling of patient samples (blood, urine and biopsy samples) might facilitate a precision (personalized) medicine approach for the treatment of DKD.

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Fig. 1: Molecular mechanisms of diabetic kidney disease.
Fig. 2: The effects of epigenetic modifications on chromatin structure.
Fig. 3: Epigenetic mechanisms of metabolic memory.
Fig. 4: Contribution of signalling circuits to persistent long non-coding RNA expression.
Fig. 5: Approaches to generate locus-specific genetic changes as a therapy for diabetic kidney disease.
Fig. 6: Locus-specific epigenetic changes as potential therapy for diabetic kidney disease.
Fig. 7: Epigenetic and RNA profiling to support precision medicine.

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Acknowledgements

The authors gratefully acknowledge funding from the US National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute), the Wanek Family Project to Cure Type 1 Diabetes at City of Hope and the Juvenile Diabetes Research Foundation. The authors thank S. T. Wilkinson and K. Higa (Office of Faculty and Institutional Support, Beckman Research Institute of City of Hope) for help editing the manuscript before submission.

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  1. Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Mitsuo Kato & Rama Natarajan

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  1. Mitsuo Kato
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  2. Rama Natarajan
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Both authors contributed to researching data for the article, discussing the article’s content, writing the article and reviewing and editing the manuscript before submission.

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Correspondence to Mitsuo Kato or Rama Natarajan.

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DATABASES

Nephroseq database: https://www.nephroseq.org/

Gene Expression Omnibus (GEO) database: https://www.ncbi.nlm.nih.gov/geo/

Glossary

Non-coding RNAs

(ncRNAs). An RNA molecule that is not translated into protein; ncRNAs can regulate gene expression at the transcriptional and post-transcriptional levels.

Genome-wide association studies

(GWAS). Cataloguing of genetic variants across the genomes of multiple individuals that are associated with a specific phenotype.

Enhancers

Short (50–1,500 bp) regions of DNA that can be bound by transcriptional activators to increase the transcription of a particular gene. An enhancer may be located upstream or downstream of the gene it regulates and does not have to be close to the transcription initiation site.

DNA methylation

An epigenetic modification that adds a methyl (CH3) group to DNA, typically at the 5′-cytosine (C) of CpG dinucleotides.

Histone post-translational modifications

(PTMs). Covalent modifications (for example, methylation, phosphorylation and acetylation) on histone residues that facilitate epigenetic regulation of gene expression by altering chromatin structure or recruiting chromatin modifiers.

Genomic imprinting

A phenomenon whereby maternal and paternal chromosomes (or genes) are differentially marked and either maternal or paternal genes are selectively suppressed. DNA methylation is a key mark for genomic imprinting.

Elongation

A process of copying DNA into the growing RNA chain by RNA polymerase during the elongation phase of transcription.

Alternative splicing

A process that allows multiple mRNAs to be transcribed from a single gene. Usually, certain exons of a gene are included or excluded from the final processed mRNA.

Histone deacetylase

(HDAC). Enzyme that removes the acetyl group from histones.

Epigenome-wide association studies

(EWAS). Cataloguing of epigenetic marks (typically focused on DNA methylation) across the genomes of multiple individuals that are associated with a specific phenotype.

ENCODE

(Encyclopedia of DNA Elements). A public research consortium funded by the National Human Genome Research Institute to systematically identify all functional elements in the human and mouse genomes.

Methylated DNA immunoprecipitation sequencing

(Me-DIP-seq). A method to identify the profile of genome-wide DNA methylation by sequencing DNA immunoprecipitated with antibody to 5-methylcytosine (5mC).

Reduced representation bisulfite sequencing

(RRBS-seq). A technique for analysing the genome-wide DNA methylation profiles with single-nucleotide resolution at relatively low cost. It combines restriction enzyme and bisulfite sequencing to enrich (~1% of genome) for areas of the genome with a high CpG content.

Whole-genome bisulfite sequencing

The gold standard method for the analysis of DNA methylation of single cytosines at base resolution in the whole genome. It involves next-generation sequencing of bisulfite-converted DNA. Sodium bisulfite converts unmethylated cytosine into uracil, which eventually will appear as thymine after sequencing. Methylated cytosines appear as cytosine.

Epigenotype

Encompasses a set of epigenetic marks (DNA methylation and histone modifications) unique to specific cells or individuals that determine their cell fate or phenotypes (disease susceptibility), respectively.

Chromatin immunoprecipitation (ChIP) followed by sequencing

(ChIP–seq). A method to analyse protein interactions with DNA. ChIP–seq combines ChIP using specific antibodies to a target protein followed by high-throughput DNA sequencing to identify the binding sites of DNA-associated proteins in a genome-wide fashion.

Mediator complexes

A multiprotein complex that is required for gene transcription by RNA polymerase II and functions as a transcriptional co-activator in eukaryotes. Subunits of the complex relay information from signals and transcription factors to the RNA polymerase II machinery to control the expression of specific genes.

Poised promoters

Promoters that are defined by the simultaneous presence of histone modifications associated with both gene activation and repression (bivalent). They are frequently found at the promoters and enhancers of developmental and lineage-specific genes.

Pyroptosis

A process of pro-inflammatory programmed cell death that is also a form of regulated necrosis, a lytic type of cell death inherently associated with inflammation.

Foam cells

Lipid-laden macrophages that serve as the hallmark of early-stage atherosclerotic lesion formation.

Exosomes

Cell-derived vesicles that are present in biofluids, including blood, urine, cerebrospinal fluid and conditioned medium of cultured cells. The diameter of exosomes is 30–100 nm.

Locked nucleic acid

(LNA). A modified RNA nucleotide in which the ribose moiety is modified with an extra bridge connecting the 2′ oxygen and 4′ carbon. The bridge ‘locks’ the ribose in the 3′-endo conformation, which is often found in the A-form duplexes. LNA nucleotides are very stable and have high affinity for target DNA or RNA residues, to which they hybridize.

Antagomirs

Small synthetic RNAs that are designed to silence endogenous microRNAs.

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Kato, M., Natarajan, R. Epigenetics and epigenomics in diabetic kidney disease and metabolic memory. Nat Rev Nephrol 15, 327–345 (2019). https://doi.org/10.1038/s41581-019-0135-6

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