RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse

Nature. 2006 May 25;441(7092):469-74. doi: 10.1038/nature04674.


Paramutation is a heritable epigenetic modification induced in plants by cross-talk between allelic loci. Here we report a similar modification of the mouse Kit gene in the progeny of heterozygotes with the null mutant Kit(tm1Alf) (a lacZ insertion). In spite of a homozygous wild-type genotype, their offspring maintain, to a variable extent, the white spots characteristic of Kit mutant animals. Efficiently inherited from either male or female parents, the modified phenotype results from a decrease in Kit messenger RNA levels with the accumulation of non-polyadenylated RNA molecules of abnormal sizes. Sustained transcriptional activity at the postmeiotic stages--at which time the gene is normally silent--leads to the accumulation of RNA in spermatozoa. Microinjection into fertilized eggs either of total RNA from Kit(tm1Alf/+) heterozygotes or of Kit-specific microRNAs induced a heritable white tail phenotype. Our results identify an unexpected mode of epigenetic inheritance associated with the zygotic transfer of RNA molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / embryology
  • Embryo, Mammalian / metabolism
  • Epigenesis, Genetic / genetics*
  • Female
  • Genotype
  • Heredity / genetics*
  • Male
  • Mice
  • Mutation / genetics*
  • Phenotype
  • Proto-Oncogene Proteins c-kit / genetics*
  • RNA / genetics*
  • RNA / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Spermatozoa / metabolism


  • RNA, Messenger
  • RNA
  • Proto-Oncogene Proteins c-kit