A unified framework governing the establishment and maintenance of transgenerational epigenetic inheritance

Transgenerational epigenetic inheritance (TEI) is the transfer of nongenetic information between generations. In Caenorhabditis elegans, RNA interference (RNAi) is a conserved process initiated by double-stranded RNA, which can induce TEI. While many factors have been implicated in TEI, whether they act in establishment or maintenance of the transgenerational signal, and the generation in which they act, has not been defined. Here, we characterize the actions of glh-1, hrde-1, -2, -4, morc-1, nrde-1, -2, -4, set-25, -32, wago-1, -4, znfx-1, pup-1, and emb-4 within RNAi-induced TEI. We show that these genes can be classified into 3 groups: those involved in only establishment or maintenance, or those involved in both. We identify a heterochromatin-based pathway established in the P0 generation by histone methyltransferases and maintained in later generations by MORC-1, upstream of HRDE-1-dependent silencing. By investigating lineage dynamics, we provide evidence that inheritance patterns are partially determined in RNAi-exposed parents, but that variation between offspring also contributes. And finally, we demonstrate that polyUG RNAs broadly correlate with, but do not define, inheritance patterns. Together, this work forms a cohesive model of RNAi-induced TEI.