Epigenetics: a new way to look at kidney diseases

Abstract

Only a few percent of the 3 billion pairs of chemical letters in the human genome is responsible for protein-coding sequences. Recent advances in the field of epigenomics have helped us to understand how most of the remaining sequences are responsible for gene regulation at baseline and in disease conditions. Here we discuss recent advances in the area of epigenetics--specifically in cytosine modifications--and its application in the field of nephrology.

Keywords: chronic kidney disease; cytosine methylation; enhancers; epigenetics.

FIGURE 1:

Mechanisms of DNA methylation and active demethylation. (a) DNA cytosine methylation is established using DNMT3A and 3B. During DNA replication, cytosines on the nascent strand are not methylated. DNMT1 recognizes hemimethylated DNA, sits at the replication fork and methylates the cytosines according to the template methylation status. (b) Active demethylation. Global cytosine methylation levels have been shown to decrease with aging. The speed of losing methylation is higher than that of passive demethylation, and therefore, two major pathways have been discovered: one pathway is using the TET enzyme that hydroxylates methylated cytosine. The hydroxy-methyl cytosine is further recognized by DNA glycosylases and removed from the sugar-phosphate backbone. The second pathway involves proteins such as AID that induce a base pair mismatch. Different DNA repair mechanisms are involved after the base is removed.

FIGURE 2:

The role of cytosine methylation in gene regulation. (a) Cytosine methylation of enhancer regions. Enhancer regions contain TF binding sites. When these regions are unmethylated, TFs can bind and prevent DNMT from methylating the same region. When these regions are methylated by DNMTs, MBD can recognize the methylated sequences and further associate to other factors. (b) Promoter methylation. Mostly, inversely related to transcript levels. (c) Gene body methylation. Cytosine methylation of exonic regions can potentially increase the RNAPol II transcription efficiency by inhibiting CTCF binding. In contrast, when CTCF binds to unmethylated exonic regions, it hinders the RNAPol II transcription causing RNAPol II pausing.

FIGURE 3:

Cytosine methylation changes in CKD. (a) DMRs between CKD and control human kidney tubules. In CKD, most DMRs are hypomethylated (∼70%). (b) Annotation of the DMRs using a chromatin annotation map, which was generated from histone tail modification ChIP-seq and the ChromHMM algorithm. Most of the DMRs are on enhancers. (c) A hypothetical model of our findings; enhancer DMRs might modify TF binding and thereby affect the expression of downstream transcript levels. The DMRs were located mainly at candidate enhancers. Several consensus TF-binding motifs were found in DMRs, including key renal TFs (HNF, TCFAP, SIX2). Cytosine methylation levels correlated with gene expression changes.