Recovery from transgenerational RNA silencing is driven by gene-specific homeostasis

Abstract

Gene silencing is a significant obstacle to genome engineering and has been proposed to be a non-self response against foreign DNA 1,2,3,4 . Yet, some foreign genes remain expressed for many generations 1,3,4 and some native genes remain silenced for many generations 1,5,6 . How organisms determine whether a sequence is expressed or silenced is unclear. Here we show that a stably expressed foreign DNA sequence in C. elegans is converted into a stably silenced sequence when males with the foreign DNA mate with wild-type hermaphrodites. This conversion does not occur when the hermaphrodite also has exonic sequences from the foreign DNA. Once initiated, silencing persists for many generations independent of mating and is associated with a DNA-independent signal that can silence other homologous loci in every generation. This mating-induced silencing resembles piRNA- generations. Thus, our results reveal the existence of a mechanism that maintains gene silencing initiated upon ancestral mating. By allowing retention of potentially detrimental sequences acquired through mating, this mechanism could create a reservoir of sequences that contribute to novelty when activated during evolution. ResultsMating is routinely used to introduce genes, including fluorescent reporters, into different genetic backgrounds and it is generally assumed that gene expression is unaffected by this manipulation. While

Replicating and Cycling Stores of Information Perpetuate Life

“…Nevertheless, cases of persistent non‐genetic changes − some lasting for tens to hundreds of generations (e.g., Ref. ) − provide us with opportunities to analyze how non‐genetic aspects of the cell code can be reconfigured.…”

“…Cases of indefinite persistence of change (i.e., large n ) could reflect establishment of a new set point for transgenerational homeostasis. Non‐genetic changes that persist for a few or for hundreds of generations have been detected in some organisms, but the reasons for susceptibility to change, persistence of change, or homeostatic return to ancestral states after a period of change are unknown.…”

Replicating and cycling stores of information perpetuate life

“…This developmental reprogramming thus preserves the cell code and opposes transgenerational epigenetic changes. Nevertheless, cases of persistent non-genetic changes -some lasting for tens to hundreds of generations (e.g., Vastenhouw et al, 2006;; Ashe et al, 2012;; Buckley et al, 2012;; Luteijn et al, 2012;; Shirayama et al, 2012;; de Vanssay et al, 2012;; Devanapally et al, 2015;; Leopold et al, 2015;; Minkina and Hunter, 2017;; Lev et al, 2017;; Ciabrelli et al, 2017;; Devanapally et al, 2017) - provide us with opportunities to analyze non-genetic aspects of the cell code (Figure 3).…”