Abstract
Developmental 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.
