A circadian-like gene network programs the timing and dosage of heterochronic miRNA transcription during C. elegans development.

Development relies on the exquisite control of both the timing and the levels of gene expression to achieve robust developmental transitions. How cis - and trans -acting factors control both aspects simultaneously is unclear. We show that transcriptional pulses of the temporal patterning microRNA (miRNA) lin-4 are generated by two nuclear hormone receptors (NHRs) in C. elegans , NHR-85 and NHR-23, whose mammalian orthologs, Rev-Erb and ROR, function in the circadian clock. Although Rev-Erb and ROR antagonize each other to control once-daily transcription in mammals, NHR-85/NHR-23 heterodimers bind cooperatively to lin-4 regulatory elements to induce a single pulse of expression during each larval stage. Each pulse's timing, amplitude, and duration are dictated by the phased expression of these NHRs and the C. elegans Period ortholog, LIN-42, that binds to and represses NHR-85. Therefore, during nematode temporal patterning, an evolutionary rewiring of circadian clock components couples the timing of gene expression to the control of transcriptional dosage. [Display omitted] • lin-4 miRNA transcription is highly dynamic, with ∼100 min pulses per larval stage • NHR-85/NHR-23 heterodimers bind cooperatively to the upstream lin-4 enhancers • The duration of NHR-85/NHR-23 dimerization controls lin-4 transcriptional dynamics • LIN-42 binds directly to NHR-85 to dynamically modulate lin-4 transcriptional dosage Kinney, Sahu, et al. report that genes implicated in mammalian circadian transcription are rewired in C. elegans to generate the oscillatory transcriptional patterns of miRNAs that program temporal patterning during post-embryonic development. This gene regulatory network directly controls lin-4 gene dosage in the heterochronic pathway, maintaining developmental robustness. [ABSTRACT FROM AUTHOR]