A circadian-like gene network regulates heterochronic miRNA transcription inC. elegans

Developmental robustness relies on precise control of the timing and order of cellular events. In C. 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 cycle 1-4 . How these transcriptional patterns are generated and how microRNA dosage is controlled is unknown. Here we show that transcriptional pulses of the lin-4 heterochronic 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 transcription 5-7 , we find that NHR-85 and NHR-23 bind cooperatively as heterodimers to lin-4 regulatory elements to induce a single brief pulse of expression during each larval stage. We demonstrate that the timing and duration of lin-4 transcriptional 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 in C. 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.