The skin of C. elegans, composed of a cuticle and the underlying epidermis, undergoes regular cycles of regeneration, the molt. These cycles involve extensive rhythmic accumulation of mRNAs, affecting thousands of genes or ~25% of the transcriptome. Yet, the 'molting clock' that generates rhythmicity and directs timely molts has remained elusive. Here, we provide insight into its molecular components and function. We also argue that the molting clock is not a nematode-specific invention but that similar mechanisms account for rhythmic skin regeneration across the animal kingdom. Specifically, in a targeted screen, we identified BLMP-1 through its defect in molting timing. We show that BLMP-1 accumulates and functions rhythmically and that its loss causes slow and asynchronous progression through the molting cycle and impairs cuticular barrier function. These phenotypes result from perturbed oscillatory gene expression. Thus, by combining ChIP-seq and temporally resolved gene expression profiling, we identify a set of 250 BLMP-1 target genes of which nearly 90% are oscillating genes. Reflecting BLMP-1's rhythmic activity, these genes exhibit a clear peak phase preference (i.e., their expression peaks at a specific time relative to the larval development cycle). A larger set of 1,400 genes is also dysregulated upon loss of BLMP-1 and contains >70% oscillating genes, but these are not bound by BLMP-1 and, accordingly, lack such a peak phase signature. We conclude that BLMP-1 functions both in generating oscillations, as a putative core clock gene, and in relaying them to a specific set of oscillator output genes, among which molting/cuticle genes are vastly overrepresented. These activities ensure timely molting and an intact skin barrier. Strikingly, the
blmp-1 orthologue Prdm1/Blimp1 is dynamically expressed in different mouse skin compartments, including hair follicles. Postnatal mammalian hair follicles undergo regular regenerative cycles of growth and regression under the control of a clock of unknown mechanism, and this rhythmicity, and skin barrier function, are both perturbed in Prdm1 mutant mice. Similar observations apply to additional hits from our screen. Hence, we propose that we have identified components of an evolutionarily conserved skin regeneration clock. These findings further suggest that despite its simplicity, the C. elegans skin is a powerful experimental model of animal skin regeneration.