Final Report Summary - TRANSGENERATIONALRNA (RNA-Mediated Inheritance of Acquired Traits)
Using Caenorhabditis elegans nematodes we have shown that worms transmit acquired information across many generations in the form of small RNA molecules. We found that heritable small RNAs are transcribed in response to different environmental challenges (e.g. starvation), and that these molecules controls genes in the progeny to prepare the offspring for similar hardships. We uncovered intriguing molecular mechanisms that depict a complicated picture: heritable small RNAs travel to the nucleus where they base-pair with nascent transcripts and guide methyltransferases that modify the targets’ histones. Chromatin modifications feedback to promote or restrict additional rounds of small RNA biogenesis and inheritance. Outside of the nucleus, small RNAs are amplified by RNA-dependent RNA polymerases (RdRPs), and the progeny’s pool of heritable small RNAs is sorted and shaped by liquid-like germ granules. The action of ancestral germ granules in paternal and maternal lineages generates distinct transgenerational silencing dynamics that deviate from Mendelian inheritance, and last tens of generations. Heritable endogenous small interfering RNAs regulate the transcription of thousands of genes in ways which are only partially understood, and dedicated factors are required specifically for RNA inheritance. Our work has shown that heritable RNAi persists transgenerationally owing to RdRP-mediated amplification. We identified a dedicated mechanism which determines the duration of each heritable response, and found that despite the amplification process, RNAi inheritance typically terminates in wild type worms after 3-5 generations, since an active process that we envision to act as a “Transgenerational Timer” restricts the heritable response. This “Timer” can be recalibrated to extend RNAi inheritance, and in certain cases RNAi generates stable responses (lasting hundreds of generations). We identified genes that function specifically to promote or restrict small RNA inheritance, and discovered that stress (e.g. starvation, heat, high salt) can “re-set” heritable small RNA programs, adapting the progeny to environments that differ from the environment of the ancestors. Last, we recently discovered that the worms’ nervous system sends signals to the germline which alter the heritable small RNA pool in the germline. By regulating genes transgenerationally using this mechanism, the worm’s “brain” controls the behavior of the descendants. Our discoveries suggests that small RNA inheritance is an evolved, dedicated, and tightly regulated mechanism.