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

Abstract

3 Paramutation, first observed in maize 1 and subsequently in a variety of plants 2 , is a heritable epigenetic change of the phenotype of a "paramutable" allele, initiated by interaction in heterozygotes with a "paramutagenic" form of the locus. Often referred to as an exception to the law of Mendel, which states that genetic factors segregate unchanged from heterozygotes, paramutation is meiotically stable and inherited in the absence of the inducing allele. To date, the closest observations in an animal species were changes in the DNA methylation profiles directed by the allelic locus in the mouse that we and others described as "transvection" or "paramutation-like" effects 3,4 . We now report a modification in the phenotypic expression of the wild type allele of the Kit receptor gene in the progeny of heterozygotes with a null insertion mutant. The "paramutated (Kit*)", genotypically wild type animals, maintain the white-spotted phenotype characteristic of Kit mutants in the absence of the mutant allele. The efficient paternal and maternal inheritance of the paramutated state raises the question of a possible molecular support of the epigenetic information. Non-Mendelian phenotype distributionThe tm1Alf mutation (MGI:2449782, initially designated Kit W-LacZ ) was engineered 5 by inserting a 3 kb Neo-LacZ cassette downstream of the initiator ATG. A unique mRNA of the same size with the ß-galactosidase coding sequence is expressed under control of the Kit promoter and regulatory sequences. The mutation abrogates the synthesis of the Kit tyrosine kinase receptor, which plays a critical role in several developmental processes including germinal differentiation, hematopoiesis and melanogenesis. Accordingly, Kit tm1Alf homozygotes die shortly after birth and heterozygotes show a white tail tip and white feet (Fig. 1). We initially observed an abnormal segregation of phenotypes in the progeny of crosses between two heterozygous parents. Wild type genotypes were identified by the absence of both LacZ sequences determined by genomic PCR analysis and ß-galactosidase expression by in situ X-Gal staining (not shown), and further confirmed by Southern blot analysis (Fig. 1c).However, it was striking that most of these genetically Kit +/+ mice maintained the white patches characteristic of the parental heterozygotes ( Fig. 1 and Table 1). The occurrence of this modified, "paramutated" form of the Kit + allele (Kit* phenotype) was not restricted to the progeny of heterozygote intercrossing, but also observed in Kit tm1Alf / + crosses with wild type partners, 4 independently of the gender combination (Table 1). It was not dependent on the genetic background of the mice since the same phenotypes were found with the original 129/Sv Kit tm1Alf / + heterozygotes and after at least 6 generations of back-crosses of the mutation onto the C57Bl/6 and B6D2 genetic backgrounds (Supplementary Table 1). The paramutated phenotype was inherited, with a variable phenotypic extent depending on the crosses (Supplementary Fig. 1). It was mos...

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

“…Alternatively, intergenerational effects could result if RNAs carry sequence-specific information to gametes through circulation from distant tissues that experience chemicals, changes in diet, or stress. In support of this possibility, studies focused on intergenerational and transgenerational effects in mammals implicate RNA in the inheritance of gene expression states across generations (47), report changes in small RNAs in gametes (48,49), and report changes in RNAs acquired during gamete maturation from surrounding epithelia (50,51). However, in all these cases, direct effects of a treatment-e.g., diet-on gametes and surrounding support tissues that alter RNA composition in gametes have not been ruled out.…”

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…Epigenetic inheritance has been demonstrated in several species including worm (2), fly (3) and mouse species (4,5). Epigenetic inheritance can be modulated by environmental factors and transmitted to subsequent generations via germline cells (6,7).…”

Genetics of germ cell development

“…For example, the white-spotting phenotype of the Kit tm1Alf mutant in mice was found to be transmitted by abnormally retained mRNAs in sperm, providing a mechanistic basis for this case of non-Mendelian inheritance. 146 However, current understanding of the regulation of the germ cell epigenome is insufficient to provide true insight into the means by which the effects described in many of these studies might be mediated. A deeper understanding of how DNA methylation, histone modifications, and other aspects of chromatin state are regulated in the developing germline of each of these model organisms is required to fully understand the meaning of these effects.…”