L1 Retrotransposons in Human Cancers

Abstract

Retrotransposons like L1 are silenced in somatic cells by a variety of mechanisms acting at different levels. Protective mechanisms include DNA methylation and packaging into inactive chromatin to suppress transcription and prevent recombination, potentially supported by cytidine deaminase editing of RNA. Furthermore, DNA strand breaks arising during attempted retrotranspositions ought to activate cellular checkpoints, and L1 activation outside immunoprivileged sites may elicit immune responses. A number of observations indicate that L1 sequences nevertheless become reactivated in human cancer. Prominently, methylation of L1 sequences is diminished in many cancer types and full-length L1 RNAs become detectable, although strong expression is restricted to germ cell cancers. L1 elements have been found to be enriched at sites of illegitimate recombination in many cancers. In theory, lack of L1 repression in cancer might cause transcriptional deregulation, insertional mutations, DNA breaks, and an increased frequency of recombinations, contributing to genome disorganization, expression changes, and chromosomal instability. There is however little evidence that such effects occur at a gross scale in human cancers. Rather, as a rule, L1 repression is only partly alleviated. Unfortunately, many techniques commonly used to investigate genetic and epigenetic alterations in cancer cells are not well suited to detect subtle effects elicited by partial reactivation of retroelements like L1 which are present as abundant, but heterogeneous copies. Therefore, effects of L1 sequences exerted on the local chromatin structure, on the transcriptional regulation of individual genes, and on chromosome fragility need to be more closely investigated in normal and cancer cells.

Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer

“…Increased expression of repetitive DNA sequences has been frequently observed in cancer cells, and this has often been linked to changes in DNA methylation or chromatin structure (Florl et al 1999;Menendez et al 2004;Schulz 2006;Ting et al 2011). By integrating the transcriptome and epigenome data sets, our anal- …”

Long interspersed nuclear elements (LINEs) show tissue-specific, mosaic genome and methylation-unrestricted, widespread expression of noncoding RNAs in somatic tissues of the rat

“…We also observed tissue-specific methylation patterns of P1-LINE with respect to the hypermethylated 5kb Msp I band in the lungs and thymus and the hypomethylated 2.8, 1.3, 0.89 and 0.4 kb well as in other diseases such as hemophilia, Duchenne Muscular Dystrophy (DMD), β-thalassemia, chronic granulomatous disease (CGD) and Coffin-Lowry Syndrome (CLS). [59][60][61][62][63][64][65][66][67][68][69][70][71] Therefore, expression of L1s is generally correlated with genome rearrangement, genomic instability, alterations in gene expression and diseases. 72 Recently, LINEs have been reviewed as a major source of genetic disposition to diseases in humans.…”

The enemy within: An epigenetic role of retrotransposons in cancer initiation

“…By knowing the orientation and placement of an LINE-1 element (see for instance Ref. 18), with respect to a neighbouring gene, one can, in principle, predict the likely effect for a given RTN-gene pair. Multiple activations of RTNs within the genome by a severe stress, however, would produce highly complex transcriptional effects, with equally complex cellular consequences.…”

“…The idea has its most direct application to 'sporadic' cancers, which comprise approximately 80% of all clinical cases [10], and to carcinogen-induced cancers but, as discussed later, may also have relevance to cancers with some proven degree of genetic causation. In addition, the suspected genetic effects of activated RTNs in cancer [17][18][19] are briefly reviewed. The hypothesis can help explain and integrate many of the disparate observations in cancer biology that have so far resisted convincing synthesis.…”