Understanding mechanisms and functions of miRNA oscillations during development

ended

Successful development of an organism relies on careful temporal orchestration of a large number of diverse events. Although processes such as cell proliferation, migration and differentiation are thus under precise temporal control, molecular mechanisms of the relevant biological timers have remained largely enigmatic. I propose to exploit the repetitive development and robust oscillatory gene expression of the nematode C. elegans to identify fundamental principles of temporal control of organismal development through rhythmic gene expression. High temporal reproducibility of developmental progression and genetic tractability are additional major assets of this novel experimental paradigm. Previous work in my host-lab uncovered high-amplitude oscillatory expression of ~2700 genes peaking exactly once per larval stage, with an ~8-hr period. These oscillations appear to orchestrate periodic developmental events encompassing synthesis and shedding of the cuticle, cell proliferation and differentiation. A small set of regulatory miRNAs also exhibit oscillations with large amplitudes. This is surprising given that miRNAs are generally quite stable, and that the transcript level oscillations appear to be rely mostly on rhythmic transcription. Here, I propose to delineate the function of oscillatory miRNAs in rhythmic gene expression and development, and the mechanisms that render them sufficiently unstable to facilitate oscillation. Thus, through a combination of high-throughput developmental tracking, single-cell sequencing, bioinformatics, and biophysics approaches, I expect to uncover molecular mechanisms that control developmental timing and miRNA metabolism.