To make a change, we must replace old with new: plow the field to seed new plants, abandon old habits to adapt new ones, and erase the board to write down new ideas. Development is also all about change. In the very early stages of development, the mother controls virtually all aspects of animal embryogenesis: the genomes of early embryos are silent, and mRNAs and proteins that were deposited into the egg by the mother provide all functionality, from metabolism to cell division. As embryogenesis proceeds, the control over development is gradually transferred to the zygotic genome, and embryos get rid of the old maternal transcripts and replace them with newly synthesized zygotic mRNAs. This massive degradation of maternal mRNAs is a key regulatory event in early embryos, but it is poorly understood how this process is regulated.
Previous studies in flies, frogs and fish found pathways that act through specific mRNA sequences to recruit the cellular machinery and promote or inhibit mRNA decay. Such pathways include binding of the zebrafish microRNA miR-430 to hundreds of maternal mRNAs but do not explain the bulk of mRNA degradation in embryos. Therefore, we do not know the rules that decode mRNA sequences into decay patterns. In a study published in Molecular Cell (PDF), Rabani et al. address this question systems-wide.
To uncover the sequence-based rules of mRNA degradation, the authors developed UTR-Seq. UTR-Seq tests thousands of sequences in parallel for their effect on mRNA stability and then builds computational models to decode the sequence-based rules of mRNA decay. UTR-Seq revealed two temporal degradation programs during early zebrafish development: a maternally encoded early-onset program and a late-onset program that accelerated degradation after zygotic genome activation. Three signals regulated early-onset decay: stabilizing poly-U and UUAG sequences, and destabilizing GC-rich signals. Three signals explained late-onset degradation: miR-430 binding sites, AU-rich sequences and recognition sites for members of the Pumilio family. The resulting computational models established sequence-based rules that were able to predict the kinetics of mRNA decay during early zebrafish embryogenesis. Their application led to the successful design of artificial mRNAs with predetermined decay dynamics in early embryos: mutating or introducing specific sequences generated mRNAs with pre-determined decay profiles. Finally, the UTR-Seq method is broadly applicable in many biological systems to discover sequence-to-activity RNA regulatory relationships.