RNA memories: trans-generational epigenetic inheritance of RNA-mediated gene silencing

Trans-generational epigenetic inheritance (TEI), which functionally intersects RNA with histone modification, recently forced a reinterpretation of the interplay between gene expression and selective pressures. Our groups integrate genetic, genomic, dynamic imaging, biochemistry and proteomic technologies to provide a functional mechanistic understanding of the interplay of TEI and the RNA interference (RNAi) phenomena in the nematode C. elegans. We discovered a family of proteins (the nuclear Argonaute-interacting proteins or NIPs), which controls the strength, inheritance and gene target specificity of nuclear RNAi. Loss of NIP-1 and NIP-2 in the soma leads to an enhancement of nuclear RNAi activities without affecting cytoplasmic RNAi. Loss of NIP-3 in the germline disables TEI and leads to a profoundly impaired response to transposable genomic elements (viral-like sequences). The genome of nip-3 mutants becomes de-stabilized; spontaneous visible mutations arise at high frequency due to an unbridled mobilization of a subset of transposable elements. Surprisingly, silencing of a distinct subset of transposable elements is coincidentally enhanced. Finally, expression imaging revealed an eminent role for the maturing male germline in TEI. This data supports a model wherein NIPs determine the potency and stability of TEI by gating and sorting small RNAs (which provide specificity) towards germline and somatic nuclear RNAi and epigenetic machineries. Our work further implies that this molecular machinery evolved to atone an animal's epigenetic memory to preserve a species' integrity in face of genetic pathogens. Overall design: Examination of three novel candidates in transgenerational epigenetic inheritance in the nematode C. elegans.