Conservation of mRNA operon formation in control of the heat shock response in mammalian cells

Prokaryotes use polycistronic transcription (operons) to express multiple messenger RNAs (mRNAs) from a single promoter to coexpress functionally related genes. However, how do eukaryotes, which express monocistronic messages, achieve the same regulation? Previously, we demonstrated that yeast uses RNA operons, i.e., mRNAs assembled in trans (transperons), to control multiple cellular pathways such as the heat shock response (HSR). As the HSR is conserved from yeast to mammals, we used single-molecule RNA labeling and pulldown techniques to demonstrate that mammalian heat shock protein (HSP) mRNAs also form operons upon transcription during heat stress. HSP RNA operon formation is dependent on the heat shock factor 1 transcription factor and intra- and interchromosomal interactions between the HSP genes. Work in yeast identified a conserved RNA sequence motif and histone H4 functions that act downstream thereof to regulate transperon assembly. Our work highlights the evolutionarily conserved regulation of the HSR and for RNA operons in eukaryotic gene regulation.