A developmental timer coordinates organism-wide microRNA transcription

Abstract

The development of distinct tissues must be precisely coordinated to ensure that growth and cell fate transitions occur in the correct temporal order across the organism, yet the mechanisms that coordinate these timing events remain unclear. In Caenorhabditis elegans, stage-specific cell fate transitions are driven by pulsatile transcription of heterochronic microRNAs, but the source of these rhythms has been unknown. Here, we identify a developmental timer composed of the transcription factor MYRF-1 and the PERIOD-like repressor LIN-42 that operates in all somatic cells. MYRF-1 binds conserved regulatory elements upstream of heterochronic microRNA genes and drives synchronized, once-per-stage transcriptional pulses across tissues, while concurrently activating lin-42 expression. Newly synthesized LIN-42 directly associates with MYRF-1, limiting its nuclear residence and transcriptional activity to constrain the amplitude and duration of each transcriptional burst. This reciprocal transcriptional/translational feedback loop generates organism-wide, phase-locked microRNA expression, coupling tissue-specific development to organismal growth through a shared timing mechanism.