miRhythm · Understanding mechanisms and functions of miRNA oscillations during development
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-01-01 → 2022-08-02
- EU contribution
- €203,149
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Understanding mechanisms and functions of miRNA oscillations during development
Many biological systems exhibit rhythmic behaviors, ranging from circadian rhythms, heart muscle contraction, neuron firing, hormone production, to cell divisions. Rhythmic gene expression may drive such behaviors, as illustrated by the oscillations that drive repetitive somite (and ultimately vertebrae) formation during vertebrate development, or the ~24-hour rhythms of the circadian clocks that provide a schedule for cellular, tissue, and organismal activities in animals. Perturbations to these time-keeping mechanisms are an invitation to diseased states. Hence, it is important to understand the physiological function and the pathological aberrations of such mechanisms. Cellular components such as transcription factors and signaling proteins are well known as important components of gene expression oscillators. We focused on miRNAs, a type of non-coding RNA that is important in regulating gene expression post-transcriptionally, but not known to function very dynamically. We had observed that some miRNAs undergo rhythmic accumulation with a short, ~8-hour period during development of the nematode C. elegans. We hypothesized that these “oscillating miRNAs” would function dynamically and help to time development. We proposed to investigate the functions of these miRNAs as well as the mechanisms that generate and shape these oscillations in the first place. We set the following objectives to dissect the role of oscillating miRNAs in C. elegans development and to characterize the mechanism: (i) to characterize developmental functions of oscillating miRNAs (osc-miRs) and their rhythmic expression (ii) to identify osc-miR targets (iii) to elucidate the mechanisms of miRNA oscillation We discovered cellular mechanisms that can promote oscillatory miRNA expression while ruling out others. We also investigated what happens when miRNA activity is lost or disrupted, and how it affects organism development in physiological and non-physiological settings. Our findings support the notion that miRNAs can function very dynamically to shape developmental processes, expanding our understanding of this biomedically important class of gene regulators and developmental timing processes.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION · BASELCoordinatorSwitzerland
Links
Data: CORDIS, © European Union