Genetic compensation in β-actin mutants occurs independently of mutations that destabilize β-actin mRNA

Abstract

Proper maintenance of gene expression in response to mutations or environmental fluctuations is critical for cell development and survival. Recently, a novel genetic compensation mechanism was described wherein mutant mRNA decay triggers increased transcription of paralogous genes. This effect was reported for several genes, including {beta}-actin (Actb) in mouse embryonic stem cells, where Actb mRNA with a premature termination codon enhances transcription of its paralog, {gamma}-actin (Actg1), and partially rescues cytoskeletal defects. Here we show that, in both mouse and human embryonic stem cells, mutations in the ACTB gene, regardless of mutant mRNA expression, trigger genetic compensation. Furthermore, transgenic expression of mutant ACTB mRNA with a premature stop codon fails to induce genetic compensation. Depletion of the SRF or MRTF-A transcription factors, which are known to increase ACTB transcription in response to low ACTB protein levels, diminishes the genetic compensation response in ACTB mutants. These results suggest that genetic compensation in ACTB mutants is primarily mediated by a transcriptional feedback loop via SRF/MRTF-A, independent of the expression or degradation of mutant ACTB mRNA.