科研之友
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摘要
Transgenerational epigenetic inheritance (TEI) is the inheritance of epigenetic information for two or more generations. In most cases, TEI is limited to a small number of generations (2-3). The short-term nature of TEI could be set by innate biochemical limitations to TEI or by genetically encoded systems that actively limit TEI. dsRNA-mediated gene silencing (RNAi) can be inherited in Caenorhabditis elegans (termed RNAi inheritance or RNA-directed TEI). To identify systems that might actively limit RNA-directed TEI, we conducted a forward genetic screen for factors whose mutation enhanced RNAi inheritance. This screen identified the gene heritable enhancer of RNAi (heri-1), whose mutation causes RNAi inheritance to last longer (>20 generations) than normal. heri-1 encodes a protein with a chromodomain and a kinase-homology domain that is expressed in germ cells and localizes to nuclei. In C. elegans, a nuclear branch of the RNAi pathway (termed the nuclear RNAi or NRDE pathway) promotes RNAi inheritance. We find that heri-1(-) animals have defects in spermatogenesis that are suppressible by mutations in the nuclear RNAi Argonaute (Ago) HRDE-1, suggesting that HERI-1 might normally act in sperm progenitor cells to limit nuclear RNAi and/or RNAi inheritance. Consistent with this idea, we find that the NRDE nuclear RNAi pathway is hyper-responsive to experimental RNAi treatments in heri-1 mutant animals. Interestingly, HERI-1 binds to genes targeted by RNAi, suggesting that HERI-1 may have a direct role in limiting nuclear RNAi and, therefore, RNAi inheritance. Finally, the recruitment of HERI-1 to chromatin depends upon the same factors that drive co-transcriptional gene silencing, suggesting that the generational perdurance of RNAi inheritance in C. elegans may be set by competing pro- and anti-silencing outputs of the nuclear RNAi machinery.
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单位university of Toronto; harvard medical school
