Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

Abstract

Retrotransposable elements comprise around 50% of the mammalian genome. Their activity represents a constant threat to the host and has prompted the development of adaptive control mechanisms to protect genome architecture and function. To ensure their propagation, retrotransposons have to mobilize in cells destined for the next generation. Accordingly, these elements are particularly well suited to transcriptional networks associated with pluripotent and germinal states in mammals. The relaxation of epigenetic control that occurs in the early developing germline constitutes a dangerous window in which retrotransposons can escape from host restraint and massively expand. What could be observed as risky behavior may turn out to be an insidious strategy developed by germ cells to sense retrotransposons and hold them back in check. Herein, we review recent insights that have provided a detailed picture of the defense mechanisms that concur toward retrotransposon silencing in mammalian genomes, and in particular in the germline. In this lineage, retrotransposons are hit at multiple stages of their life cycle, through transcriptional repression, RNA degradation and translational control. An organized cross-talk between PIWIinteracting small RNAs (piRNAs) and various nuclear and cytoplasmic accessories provides this potent and multilayered response to retrotransposon unleashing in early germ cells.

The MOV10 Helicase Inhibits LINE-1 Mobility

“…LINE-1 activity is controlled by host cells via a number of mechanisms that target distinct stages of LINE-1 replication (12). One layer of control involves methylation of LINE-1 DNA, which silences LINE-1 RNA synthesis.…”

“…The 5Ј-UTR of LINE-1 serves as an internal promoter to drive LINE-1 RNA production (13). This region contains multiple CpG islands that are subject to methylation, which suppresses LINE-1 transcription (12,14). Indeed, mutation or knock-out of the DNA methyltransferases in mice such as Dnmt1, Dnmt3A, Dnmt3B, and Dnmt3L leads to hypomethylation of LINE-1 and other transposons and concomitantly a high level expression of these elements (15)(16)(17).…”

“…LINE-1 can also modulate the expression of host genes (2). Host cells have therefore evolved a number of mechanisms to control LINE-1 replication (12). One strategy involves DNA methylation that silences LINE-1 RNA synthesis.…”

Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline

“…To successfully propagate through generations, TEs must be active in germ cells or during early embryonic development, and are therefore strongly selected for germline expression. However, several mechanisms have evolved to limit the mutagenic potential of TEs in the germline (Ollinger et al, 2010;Zamudio and Bourc'his, 2010). Mice carrying mutations in Dnmt1, or in the germline-restricted accessory factor for de novo DNA methylation Dnmt3L, lose DNA methylation at TE sequences resulting in massive upregulation of LINE1 and intracisternal A-type particle (IAP) retroelements in the developing germline (Walsh et al, 1998;Bourc'his and Bestor, 2004).…”

Conversions épigénétiques transmises de façon stable au cours des générations

“…Elle régule non seulement l'activité des éléments transposables dans la lignée germinale, mais aussi l'expression de certains gènes au cours du déve-loppement [13]. Son existence est très ancienne et elle est conservée chez les vertébrés [14]. Un système de transgènes a été utilisé par la suite pour étudier les propriétés phé-notypiques, génétiques et moléculaires de la répression de l'élément P. Dans ce système, appelé trans-silencing, un transgène inséré dans l'hétérochromatine télomérique réprime, dans la lignée germinale, un transgène homologue, quelle que soit la localisation chromosomique de ce dernier [15,16].…”