Methylation of 45S Ribosomal DNA (rDNA) Is Associated with Cancer and Aging in Humans

Abstract

Cancer and aging, two distinct processes of cell development, are two major problems threatening our human health and life in current days. Epigenetic studies, especially DNA methylation, have been intensively investigated on them over the years, though a lot of unanswered issues remain. In the human genome, rDNA is a highly conserved tandem repeat family playing critical roles in protein synthesis, genome stability and integrity, etc. More importantly, rDNA is the significant target of DNA methylation, and a potential association between rDNA methylation and cancer and aging has emerged recently. However, whether there is a general trend that rDNA methylation is associated with cancer and aging remains an open issue. In this study, the involvement of rDNA methylation in a series of records of cancer and aging was investigated and summarized, upon which perspectives about rDNA methylation in cancer and aging were proposed. The results showed that rDNA methylation in most cancer cases displayed a consistent pattern with hypermethylation in the coding region but with hypomethylation in the promoter region, which likely facilitates the proliferation and metastasis of cancerous cells. Distinctively, both the coding and promoter regions of rDNA become increasingly methylated during the process of aging, indicating the decline of rDNA activity. The finding of rDNA methylation also implies its potential application as an epigenetic biomarker in the diagnosis of cancer and aging. This work will shed light on our understanding of the pathogenesis, diagnosis, and treatment of cancer and aging from the perspective of rDNA methylation.

Human rDNA and Cancer

“…DNA methylation is one of the major factors which determine the gene expression and progression of human diseases is often accompanied by changing the rDNA methylation pattern [ 14 , 41 , 42 ]. The locus of human rDNA is distinguished by high levels of DNA methylation.…”

“…Typically, one unit contains >1500 CpG islands (i.e., >10 CpGs per 100 nt) [ 43 , 44 ]. Studies have shown that cancer correlates with altered methylation status of the rDNA locus [ 42 ]. Some of these alterations may be regarded as more or less efficient self-defence of the cell against transformation.…”

“…The distribution of the CH3 groups along the DNA strand presents a special problem. The methylation of promoter is usually believed to be a repressive epigenetic mark, although in senescent cells the rRNA coding regions are highly methylated as well [ 42 , 48 ]. Strangely enough, methylation of the ribosomal genes positively correlates with their transcription intensity, which is known as “the gene-body paradox“ [ 49 ].…”

P53 and DNA Methylation in the Aging Process

“…The study found that age-related changes in the major histocompatibility complex class 1 (MHC1) gene promoter and intra-gene methylation involved in immune function are closely related to changes in gene expression [69]. During aging, DNA methylation changes occur in tissues [70], The rDNA activity is decreased, and both its coding and promoter regions became increasingly methylated [71]. Age-related methylation was originally observed on the CpG island promoter of protein-coding genes [22] [72].…”

Genetic variation at mouse and human ribosomal DNA influences associated epigenetic states

“…Indeed, rDNA clusters are typically excluded from genome assemblies, and none of the large-scale genomic analyses of recent years have yielded any insights into rDNA genetic variation. Nonetheless, several smaller studies have noted not only inter-individual genetic variation (in both sequence and copy number) in mouse and human rDNA, but also epigenetic variation in the context of whole organism stress responses 2,5–8 . The latter observation raises the intriguing possibility that the impact of mammalian rDNA sequence variation is also relevant at the DNA level, thereby impacting transcriptional outputs in different biological contexts.…”