The developmentally-timed decay of an essential microRNA family is seed sequence-dependent

Abstract

MicroRNA (miRNA) abundance is tightly controlled by regulation of biogenesis and decay. Here we show that the mir-35 miRNA family undergoes regulated decay at the transition from embryonic to larval development in C. elegans. The seed sequence of the miRNA is necessary and sufficient for this regulation. Sequences outside the seed (3’ end) regulate mir-35 abundance in the embryo but are not necessary for sharp decay at the transition to larval development. Enzymatic modifications of the miRNA 3’ end are neither prevalent nor correlated with changes in decay, suggesting that miRNA 3’ end display is not a core feature of this mechanism and further supporting a seed-driven decay model. Our findings demonstrate that seed sequence-specific decay can selectively and coherently regulate all redundant members of a miRNA seed family, a class of mechanism that has great biological and therapeutic potential for dynamic regulation of a miRNA family’s target repertoire.

The catalytic activity of microRNA Argonautes plays a modest role in microRNA star strand destabilization inC. elegans

“…Comparing ebax-1(null) young adults to wild type, we corroborate the stabilization of mir-788, mir-247, mir-42, mir-230, mir-797, mir-43 and mir-253 in this mutant as previously observed (Figure S4, Table S13) (91). (Note that mir-35-41 are not highly expressed in these samples, which do not contain embryos, in contrast to the previous studies of ebax-1(null) which examined gravid adults or embryos (91,92).) Next, ebax-1(null) was introduced to the alg-1(AEDH); alg-2(AEDH) background, and miRNA abundances were compared to ebax-1(null) single mutants.…”

“…While we explored a model of enhanced TDMD in the absence of slicing, this was not borne out. However, conventional TDMD has yet to be demonstrated in C. elegans (69, 92, 96), so the pathways of slicing and TDMD may not be competing in this context as might be expected in other systems (72, 77–91). Because of the modest reduction of these few guide strands, we posit that slicing is not central to their biogenesis.…”