Where to Draw the LINE—Are Retrotransposable Elements Here to Stay?

SIMPLE SUMMARY: Colorectal cancer incidence has increased in young adults over the last decade. Such a shift in epidemiology suggests increased environmental risk factors play a prominent role in the onset of the disease. DNA methylation is one of several aspects of the epigenome that are frequently mutated in cancer and that function in the silencing of endogenous viral repeats, also known as transposable elements. Here we discuss the findings from a recent mapping effort of Long Interspersed Nuclear Elements 1 (LINE1) transposition events over a lifetime in the colonic epithelium, which revealed increased levels of transposition in human colorectal tumors. These findings shed light on LINE1 retrotransposition in colorectal tumors and how it may be crucial in developing future therapeutic avenues. ABSTRACT: The frequency of somatic retrotranspositions of Long Interspersed Nuclear Elements 1 (LINE1) over a lifetime in healthy colonic epithelium and colorectal tumors has recently been reported. Indicative of a cell type-specific effect, LINE1 sequences in colonic epithelium showed lower levels of DNA methylation compared to other cell types examined in the study. Consistent with a role for DNA methylation in transposon silencing, the decreases in DNA methylation observed at LINE1 elements in colonic epithelium were accompanied by increases in LINE1 mRNA levels. In human primary colorectal tumors, LINE1 retrotransposition frequency was tenfold higher than in normal colonic tissues, with insertions potentially altering genomic stability and cellular functions. Here, we discuss the discoveries made by Nam and colleagues, emphasizing the intestinal-specific methylation signature regulating the LINE1 lifecycle and how this new information could shape future drug discovery endeavors against colorectal cancer.