MIWI2 and MILI Have Differential Effects on piRNA Biogenesis and DNA Methylation

Cell Rep. 2015 Aug 25;12(8):1234-43. doi: 10.1016/j.celrep.2015.07.036. Epub 2015 Aug 13.


In developing male germ cells, prospermatogonia, two Piwi proteins, MILI and MIWI2, use Piwi-interacting RNA (piRNA) guides to repress transposable element (TE) expression and ensure genome stability and proper gametogenesis. In addition to their roles in post-transcriptional TE repression, both proteins are required for DNA methylation of TE sequences. Here, we analyzed the effect of Miwi2 deficiency on piRNA biogenesis and transposon repression. Miwi2 deficiency had only a minor impact on piRNA biogenesis; however, the piRNA profile of Miwi2-knockout mice indicated overexpression of several LINE1 TE families that led to activation of the ping-pong piRNA cycle. Furthermore, we found that MILI and MIWI2 have distinct functions in TE repression in the nucleus. MILI is responsible for DNA methylation of a larger subset of TE families than MIWI2 is, suggesting that the proteins have independent roles in establishing DNA methylation patterns.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism*
  • Base Sequence
  • DNA Methylation*
  • DNA Transposable Elements / genetics
  • Long Interspersed Nucleotide Elements / genetics
  • Male
  • Mice
  • Molecular Sequence Data
  • RNA, Small Interfering / genetics*
  • Spermatogonia / metabolism


  • Argonaute Proteins
  • DNA Transposable Elements
  • PIWIL4 protein, mouse
  • Piwil2 protein, mouse
  • RNA, Small Interfering