Circadian rhythm orthologs drive pulses of heterochronic miRNA transcription in C. elegans

AbstractDevelopmental robustness relies on precise control of the timing and order of cellular events. InC. elegans, the invariant sequence of post-embryonic cell fate specification is controlled by oscillatory patterns of heterochronic microRNA transcription that are phase-locked with the larval molting cycle1-4. How these transcriptional patterns are generated and how microRNA dosage is controlled is unknown. Here we show that transcriptional pulses of thelin-4heterochronic microRNA are produced by two nuclear hormone receptors, NHR-85 and NHR-23, whose mammalian orthologs, Rev-Erb and ROR, function in the circadian clock. While Rev-Erb and ROR play antagonistic roles in regulating once-daily transcription5-7, we find that NHR-85 and NHR-23 bind cooperatively as heterodimers tolin-4regulatory elements to induce a single brief pulse of expression during each larval stage. We demonstrate that the timing and duration oflin-4transcriptional pulses are programmed by the phased overlap of NHR-85 and NHR-23 protein expression and that these regulatory interactions are post-transcriptionally controlled by LIN-42, the circadian Period ortholog inC. elegans. These findings suggest that an evolutionary rewiring of the circadian clock machinery is co-opted in nematodes to generate periodic transcriptional patterns that define cell fate progression.