A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice

Mol Cell. 2008 Sep 26;31(6):785-99. doi: 10.1016/j.molcel.2008.09.003.


piRNAs and Piwi proteins have been implicated in transposon control and are linked to transposon methylation in mammals. Here we examined the construction of the piRNA system in the restricted developmental window in which methylation patterns are set during mammalian embryogenesis. We find robust expression of two Piwi family proteins, MIWI2 and MILI. Their associated piRNA profiles reveal differences from Drosophila wherein large piRNA clusters act as master regulators of silencing. Instead, in mammals, dispersed transposon copies initiate the pathway, producing primary piRNAs, which predominantly join MILI in the cytoplasm. MIWI2, whose nuclear localization and association with piRNAs depend upon MILI, is enriched for secondary piRNAs antisense to the elements that it controls. The Piwi pathway lies upstream of known mediators of DNA methylation, since piRNAs are still produced in dnmt3L mutants, which fail to methylate transposons. This implicates piRNAs as specificity determinants of DNA methylation in germ cells.

Publication types

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

MeSH terms

  • Animals
  • Argonaute Proteins
  • Base Sequence
  • DNA Methylation*
  • DNA Transposable Elements / genetics*
  • Drosophila melanogaster / genetics
  • Embryonic Development
  • Genome / genetics
  • Germ Cells / metabolism
  • Long Interspersed Nucleotide Elements / genetics
  • Mice
  • Models, Genetic
  • Molecular Sequence Data
  • Protein Binding
  • Proteins / metabolism
  • RNA, Small Interfering / metabolism*
  • Short Interspersed Nucleotide Elements / genetics


  • Argonaute Proteins
  • DNA Transposable Elements
  • Piwil1 protein, mouse
  • Piwil2 protein, mouse
  • Proteins
  • RNA, Small Interfering

Associated data

  • GENBANK/GSE12757