SUMMARY
Animal physiology and development both rely on biological clocks, but the extent to which feedback loops among core components of the circadian clock and conserved microRNAs operate within developmental timers is not well understood. Here, we show that a negative feedback loop between NHR-23/RORα and let-7 modulates the PER-dependent rhythm of the C. elegans molting cycle. Related quiescent intervals are delayed and protracted in nhr-23 knockdowns, advanced and abbreviated in particular let-7 mutants, and yet scheduled more regularly in double mutants. NHR-23 binds upstream ROR Response Elements (REs) and activates transcription of primary let-7 when larvae are active, whereas let-7 targets an LCS in the 3’UTR and represses expression of nhr-23 transcripts when larvae are quiescent. Moreover, NHR-23 and let-7 have scores of shared targets that are cyclically expressed and mediate related transitions in cell and animal behavior. ROREs are also found upstream of vertebrate let-7 homologs, while LCSs are found in 3’UTRs of ROR transcripts. Conservation of this feedback loop has implications for human clocks and related malignancies and disorders of sleep and metabolism.
- Abbreviations
- UTR
- Untranslated Region
- RNA
- Ribonucleic Acid
- RNAi
- RNA interference
- ROR
- Retinoid-related Orphan Receptor
- HRE
- Hormone Response Element
- NHR
- Nuclear Hormone Receptor
- PER
- PERIOD gene
- GFP
- Green Fluorescent Protein
- iCLIP
- Individual-nucleotide resolution Crosslinking Immunoprecipitation
- RORE
- ROR Response Element
- LCS
- let-7consensus site
- NHR
- Nuclear Hormone Receptor
- Mlt
- Molting Cycle Defective
- MFE
- Minimum Free Energy
- pri
- Primary
- Let
- Lethal
- CRISPR
- Clustered Regularly Interspersed Short Palindromic Repeats
- crRNA
- CRISPR RNA
- tracrRNA
- Trans-activating crRNA
- nt
- Nucleotides
- td
- Tandem
- ssODN
- Single Stranded Oligodeoxynucleotides
- VPC
- Vulval Precursor Cell