Hide and seek: how chromatin-based pathways silence retroelements in the mammalian germline

Abstract

Retroelements comprise a major fraction of most mammalian genomes. To protect their fitness and stability, hosts must keep retroelements in check in their germline. In most tissues mobile element insertions are decorated with chromatin modifications suggestive of transcriptional silencing. However, germline cells undergo massive chromatin reprogramming events, which erase repressive chromatin marks and necessitate de novo re-establishment of silencing. How do host genomes achieve the discrimination necessary for this de novo silencing? A series of recent studies have revealed aspects of the multi-pronged strategy that mammalian genomes use to identify and silence retroelements. These strategies include the use of small RNA-guides, of specialized DNA-binding protein adaptors and of proteins that repair chromatin discontinuities caused by retroelement insertions. Genetic analyses reveal the importance of these mechanisms of protection, each of which specializes in silencing retroelements of different evolutionary ages. Together, these strategies allow mammalian genomes to withstand the high burden of their parasites.

Figure 1. Three layers of retrotransposon control in the mammalian germline

(a) piRNA-mediated silencing in male germ cells. Retroelement insertions expressed in germ cells (left panel) are processed into piRNAs, which bind to PIWI proteins (middle panel). In turn, these piRNA-PIWI complexes guide the deposition of repressive chromatin marks on individual retroelement insertions. New families of retroelements can escape the piRNA pathway by changing their promoter sequences (white bars) and avoid expression in germ cells (right panel). (b) An evolutionary arms race between host KZNF proteins and retroelements. KZNF proteins bind to individual insertions via their ZNF domain (blue boxes) and trigger silencing by recruiting KAP1, HMTs and DNMTs via their KRAB domain (green box). New retroelements evade KZNFs by changing (or deleting) this binding site. Upon KZNF gene duplication and ZNF diversification a new KZNF (KZNF*) can regain control over the new element. (c) A positioneffect-variegation (PEV) like mechanism for silencing retroelements. Upon the insertion of a retroelement into a heterochromatin domain (left panel), chromatin-binding complexes (e.g., HUSH complex proteins) can read and repair these scars by ‘spreading’ heterochromatin and establish effective silencing over the element (right panel).