Loss of the Mili-interacting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile

摘要

Piwi proteins and their associated Piwi-interacting RNAs (piRNAs) are implicated in transposon silencing in the mouse germ line.There is currently little information on additional proteins in the murine Piwi complex and how they might regulate the entry oftranscripts that accumulate as piRNAs in the Piwi ribonucleoprotein (piRNP). We isolated Mili-containing complexes from adultmouse testes and identified Tudor domain–containing protein-1 (Tdrd1) as a factor specifically associated with the Mili piRNP throughout spermatogenesis. Complex formation is promoted by the recognition of symmetrically dimethylated arginines atthe N terminus of Mili by the tudor domains of Tdrd1. Similar to a Miii mutant, mice lacking Tdrdl show derepression ofL1 transposons accompanied by a loss of DNA methylation at their regulatory elements and delocalizatipn of Miwi2 from the nucleus to the cytoplasm. Finally, we show that Mili piRNPs devoid of Tdrd1 accept the entry of abundant cellular transcriptsinto the piRNA pathway and accumulate piRNAs with a profile that is drastically different from that of the wild type. Our datasuggest that Tdrd1 ensures the entry of correct transcripts into the normal piRNA pool.