Induction of a transcriptional adaptation response by RNA destabilization events

Transcriptional adaptation (TA) is a cellular process whereby mRNA-destabilizing mutations are associated with the transcriptional upregulation of so-called adapting genes. The nature of the TA-triggering factor(s) remains unclear, namely whether an mRNA-borne premature termination codon or the subsequent mRNA decay process, and/or its products, elicits TA. Here, working with mouse Actg1, we first establish two types of perturbations that lead to mRNA destabilization: Cas9-induced mutations predicted to lead to mutant mRNA decay, and Cas13d-mediated mRNA cleavage. We find that both types of perturbations are effective in degrading Actg1 mRNA, and that they both upregulate Actg2. Notably, increased chromatin accessibility at the Actg2 locus was observed only in the Cas9-induced mutant cells but not in the Cas13d-targeted cells, suggesting that chromatin remodeling is not required for Actg2 upregulation. We further show that ribozyme-mediated Actg1 pre-mRNA cleavage also leads to a robust upregulation of Actg2, and that this upregulation is again independent of chromatin remodeling. Together, these data highlight the critical role of RNA destabilization events as a trigger for TA, or at least a TA-like response.