Cleveland Clinic researchers have uncovered for the first time a link between two processes that, when dysregulated, are known to promote cancer development.
DNA methylation and alternative polyadenylation (APA) are both involved in the regulation of gene expression. DNA methylation, or the addition of a methyl group to DNA, operates as a signaling tool that cells utilize to repress or “turn off” genes. APA refers to a phenomenon in which a single gene can encode more than one RNA transcript because it contains multiple sites (i.e., distal and proximal) at which polyadenylation (the addition of a poly(A) tail to messenger RNA for stability and export for translation into a protein) can occur. Previous studies have demonstrated that dysregulation of either process can contribute to the development of cancer, but they have only been studied independently of each other.
In a recent study published in Molecular Cell, a team of researchers led by Angela Ting, PhD, Genomic Medicine Institute, investigated how DNA methylation and APA may overlap. Utilizing a genome-wide comparison of DNA methylation and polyadenylation site usage, they discovered that DNA methylation regulates APA via the transcription factor CTCF (CCCTC-binding factor) and the cohesin complex.
Specifically, they found that in the absence of DNA methylation, CTCF binds to APA control regions between two polyadenylation sites and recruits the cohesin complex to form chromatin loops that promote proximal site usage and interfere with RNA transcription elongation, an occurrence associated with cancer. In contrast, when DNA methylation occurs at APA control regions, CTCF binding is blocked, thus preventing chromatin loop formation and promoting the use of distal sites.
These findings demonstrate the important role that DNA methylation plays in ensuring diversity of the transcriptome, or the set of all RNA molecules expressed from an organism’s genes, as well as the potential disadvantages of global DNA methylation as a cancer treatment. The researchers also note that studies of DNA methylation-regulated APA genes may reveal novel therapeutic targets in different types of cancers.
This study was conducted in collaboration with Byron Lee, MD, PhD, Glickman Urological & Kidney Institute, Cardiovascular & Metabolic Sciences, and Tae Hyun Hwang, PhD, Quantitative Health Sciences. The study was funded by the VeloSano cancer research pilot award.
Image: DNA methylation-regulated alternative polyadenylation mechanism