PT  - JOURNAL ARTICLE
AU  - Orkan Ilbay
AU  - Charles Nelson
AU  - Victor Ambros
TI  - <em>C. elegans</em> LIN-28 controls temporal cell-fate progression by regulating LIN-46 expression via the 5’UTR of <em>lin-46</em> mRNA
AID  - 10.1101/697490
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 697490
4099  - http://biorxiv.org/content/early/2019/07/10/697490.short
4100  - http://biorxiv.org/content/early/2019/07/10/697490.full
AB  - LIN-28 is a conserved RNA-binding protein known for its critical roles in the C. elegans heterochronic pathway and its capacity to induce proliferation and pluripotency as well as its oncogenic potential in mammals. LIN-28 binds to the precursor of the conserved – cellular differentiation-promoting – microRNA let-7 and inhibits its maturation. LIN-28 also binds to and regulates many mRNAs in various cell types. However, the determinants and consequences of LIN-28-mRNA interactions are not well understood. Here, we report that LIN-28 in C. elegans represses the expression of LIN-46, a downstream protein in the heterochronic pathway, via the (unusually conserved) 5’ UTR of the lin-46 mRNA. We found that both LIN-28 and the 5’UTR of lin-46 are required to prevent LIN-46 expression at the L1/L2 stages and that precocious LIN-46 expression, caused by mutations in the lin-46 5’UTR, is sufficient to skip L2 stage cell-fates, resulting in heterochronic defects similar to the ones observed in lin-28(lf) animals. We hypothesize that the lin-46 5’UTR mediates LIN-28 binding to the lin-46 mRNA, which results in the repression of LIN-46 expression. Our results show that precocious LIN-46 expression alone can account for lin-28(lf) phenotypes, demonstrating the biological importance of direct (let-7-independent) regulation of target mRNAs by LIN-28.