PT  - JOURNAL ARTICLE
AU  - Orkan Ilbay
AU  - Victor Ambros
TI  - Regulation of nuclear-cytoplasmic partitioning by the &lt;em&gt;lin-28-lin-46&lt;/em&gt; pathway reinforces microRNA repression of HBL-1 to confer robust cell-fate progression in &lt;em&gt;C. elegans&lt;/em&gt;
AID  - 10.1101/698977
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 698977
4099  - http://biorxiv.org/content/early/2019/07/11/698977.short
4100  - http://biorxiv.org/content/early/2019/07/11/698977.full
AB  - MicroRNAs target complementary mRNAs for degradation or translational repression, reducing or preventing protein synthesis. In C. elegans, the transcription factor HBL-1 (Hunchback-like 1) promotes early larval (L2) stage cell-fate, and the let-7-family microRNAs temporally down-regulate HBL-1 to enable the L2-to-L3 cell-fate progression. In parallel to let-7-family microRNAs, the conserved RNA binding protein LIN-28 and its downstream gene lin-46, also act upstream of HBL-1 in regulating the L2-to-L3 cell-fate progression. The molecular function of LIN-46, and how the lin-28-lin-46 pathway regulates HBL-1, are not understood. Here, we report that the regulation of HBL-1 by the lin-28-lin-46 pathway is independent of the let-7/lin-4 microRNA complementary sites (LCSs) in the hbl-1 3’UTR, and involves a stage-specific post-translational regulation of HBL-1 nuclear accumulation. We find that LIN-46 is necessary and sufficient to prevent nuclear accumulation of HBL-1. Our results illuminate that the robust progression from L2 to L3 cell-fates depends on the combination of two distinct modes of HBL-1 down-regulation: decreased synthesis of HBL-1 via let-7-family microRNA activity, and decreased nuclear accumulation of HBL-1 via action of the lin-28-lin-46 pathway. Like HBL-1, many microRNA targets are transcription factors (TFs); and cooperation between regulation of nuclear accumulation and microRNA-mediated control of synthesis rate may be required to increase the precision of or confer robustness to down-regulation of these microRNA target TFs, which can be critical to achieve the optimal phenotypes.