LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 microRNA processing in Caenorhabditis elegans

Lehrbach, Nicolas J; Armisen, Javier; Lightfoot, Helen L.; Murfitt, Kenneth J.; Bugaut, Anthony; Balasubramanian, Shankar; Miska, Eric A.

doi:10.1038/nsmb.1675

Cited by 224 publications

(212 citation statements)

References 53 publications

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“…This finding is particularly true of let-7: its primary transcript is strongly expressed during the mid-L1 stage, two stages before the accumulation of its miRNA. This uncoupling is in part because of action of the LIN-28 RNA-binding protein blocking processing (12,13,32). Therefore, lin-42 and lin-28 work in concert to regulate let-7, acting at the transcription and processing steps, respectively, and increased pri-let-7 levels in lin-42 mutants could overwhelm the ability of LIN-28 to inhibit processing.…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans period homolog lin-42 regulates the timing of heterochronic miRNA expression

McCulloch

Rougvie

2014

Proc. Natl. Acad. Sci. U.S.A.

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MicroRNAs (miRNAs) are small RNAs that regulate gene expression posttranscriptionally via the 3′ UTR of target mRNAs and were first identified in the Caenorhabditis elegans heterochronic pathway. miRNAs have since been found in many organisms and have broad functions, including control of differentiation and pluripotency in humans. lin-4 and let-7-family miRNAs regulate developmental timing in C. elegans, and their proper temporal expression ensures cell lineage patterns are correctly timed and sequentially executed. Although much is known about miRNA biogenesis, less is understood about how miRNA expression is timed and regulated. lin-42, the worm homolog of the circadian rhythm gene period of flies and mammals, is another core component of the heterochronic gene pathway. lin-42 mutants have a precocious phenotype, in which later-stage programs are executed too early, but the placement of lin-42 in the timing pathway is unclear. Here, we demonstrate that lin-42 negatively regulates heterochronic miRNA transcription. let-7 and the related miRNA miR-48 accumulate precociously in lin-42 mutants. This defect reflects transcriptional misregulation because enhanced expression of both primary miRNA transcripts (pri-miRNAs) and a let-7 promoter::gfp fusion are observed. The pri-miRNA levels oscillate during larval development, in a pattern reminiscent of lin-42 expression. Importantly, we show that lin-42 is not required for this cycling; instead, peak amplitude is increased. Genetic analyses further confirm that lin-42 acts through let-7 family miRNAs. Taken together, these data show that a key function of lin-42 in developmental timing is to dampen pri-miRNAs levels, preventing their premature expression as mature miRNAs.M etazoan development uses both positional and temporal information to pattern life stages from the single-cell embryo to the reproductive adult. In Caenorhabditis elegans, the temporal component of postembryonic patterning is conveyed through the heterochronic gene regulatory circuit (see ref. 1 for review). A core theme of the heterochronic circuit is that a series of microRNA (miRNA) switches promote transitions from one stage to the next by negatively regulating key factors that direct stage-specific programs, thereby allowing successive temporal fates to be executed.Five conserved miRNAs, lin-4 and the let-7 family members, let-7, miR-48, miR-84, and miR-241, play prominent roles in the circuit (2-6). lin-4 appears first, midway through the L1 larval stage and guides the transition from the L1 to L2 stage (7). miR-48, miR-84, and miR-241 amass in the L2 and control the transition to the L3 stage, when let-7 levels rise dramatically and govern the switch to the L4. Mutations in these miRNAs cause the relevant transition to fail to advance. This process results in, for example, repetition of the L1-stage pattern in lin-4 mutants or L2-stage patterns in mir-48/84/241 mutants, consistent with the sequential expression of these miRNAs. Deciphering this temporal control mechanism then simplifies, to a...

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Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans period homolog lin-42 regulates the timing of heterochronic miRNA expression

McCulloch

Rougvie

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…LIN28 has been shown to act as an RNA-binding protein that regulates miRNA maturation, particularly the let-7 family [27,[29][30][31][36][37][38][39][40]. If LIN28 activity is higher in PSC derivatives, these cells would be expected to have low levels of mature let-7.…”

Section: The Lin28/let-7 Circuit In Psc Derivativesmentioning

confidence: 99%

Defining the nature of human pluripotent stem cell progeny

et al. 2011

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While it is clear that human pluripotent stem cells (hPSCs) can differentiate to generate a panoply of various cell types, it is unknown how closely in vitro development mirrors that which occurs in vivo. To determine whether human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) make equivalent progeny, and whether either makes cells that are analogous to tissue-derived cells, we performed comprehensive transcriptome profiling of purified PSC derivatives and their tissue-derived counterparts. Expression profiling demonstrated that hESCs and hiPSCs make nearly identical progeny for the neural, hepatic, and mesenchymal lineages, and an absence of re-expression from exogenous reprogramming factors in hiPSC progeny. However, when compared to a tissuederived counterpart, the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development, regardless of the type of cell generated. While pluripotent genes (OCT4, SOX2, REX1, and NANOG) appeared to be silenced immediately upon differentiation from hPSCs, genes normally unique to early embryos (LIN28A, LIN28B, DPPA4, and others) were not fully silenced in hPSC derivatives. These data and evidence from expression patterns in early human fetal tissue (3-16 weeks of development) suggest that the differentiated progeny of hPSCs are reflective of very early human development (< 6 weeks). These findings provide support for the idea that hPSCs can serve as useful in vitro models of early human development, but also raise important issues for disease modeling and the clinical application of hPSC derivatives.

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“…Another family of 3′-to-5′ exoribonucleases, encoded by the SMALL RNA DEGRADING NUCLE-ASE (SDN) genes, has been implicated in mature miRNA turnover in A. thaliana (14). In C. elegans and mammalian cells, Lin-28 (a stem-cell-specific regulator) binds the precursor of the let-7 miRNA in the cytoplasm and promotes its 3′ end uridylation by a poly(U) polymerase (15)(16)(17). This leads to precursor RNA degradation and downregulation of the let-7 miRNA.…”

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confidence: 99%

Uridylation of mature miRNAs and siRNAs by the MUT68 nucleotidyltransferase promotes their degradation in Chlamydomonas

Ibrahim

Rymarquis

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

127

185

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Regulation of gene expression by small RNAs (∼20-30 nucleotides in length) plays an essential role in developmental pathways and defense responses against genomic parasites in eukaryotes. MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) commonly direct the inactivation of cognate sequences through a variety of mechanisms, including RNA degradation, translation inhibition, and transcriptional repression. Recent studies have provided considerable insight into the biogenesis and the mode of action of miRNAs and siRNAs. However, relatively little is known about mechanisms of quality control and small RNA decay in RNA interference (RNAi) pathways. Here we show that deletion of MUT68, encoding a terminal nucleotidyltransferase in the alga Chlamydomonas reinhardtii, results in elevated miRNA and siRNA levels. We found that MUT68 plays a role in the untemplated uridylation of the 3′ ends of small RNAs in vivo and stimulates their degradation by the RRP6 exosome subunit in vitro. Moreover, RRP6 depletion also leads to accumulation of small RNAs in vivo. We propose that MUT68 and RRP6 cooperate in the degradation of mature miRNAs and siRNAs, as a quality control mechanism to eliminate dysfunctional or damaged small RNA molecules.exosome | RNA interference | miRNA quality control

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LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 microRNA processing in Caenorhabditis elegans

Cited by 224 publications

References 53 publications

Caenorhabditis elegans period homolog lin-42 regulates the timing of heterochronic miRNA expression

Caenorhabditis elegans period homolog lin-42 regulates the timing of heterochronic miRNA expression

Defining the nature of human pluripotent stem cell progeny

Uridylation of mature miRNAs and siRNAs by the MUT68 nucleotidyltransferase promotes their degradation in Chlamydomonas

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