Kim D, Grun D, van Oudenaarden A.. Dampening of expression oscillations by synchronous regulation of a microRNA and its target. Nat Genet 45: 1337-1344

1] Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [3].
Nature Genetics (Impact Factor: 29.35). 09/2013; 45(11). DOI: 10.1038/ng.2763
Source: PubMed


The complexity of multicellular organisms requires precise spatiotemporal regulation of gene expression during development. We find that in the nematode Caenorhabditis elegans approximately 2,000 transcripts undergo expression oscillations synchronized with larval transitions while thousands of genes are expressed in temporal gradients, similar to known timing regulators. By counting transcripts in individual worms, we show that pulsatile expression of the microRNA (miRNA) lin-4 maintains the temporal gradient of its target lin-14 by dampening its expression oscillations. Our results demonstrate that this insulation is optimal when pulsatile expression of the miRNA and its target is synchronous. We propose that such a miRNA-mediated incoherent feed-forward loop is a potent filter that prevents the propagation of potentially deleterious fluctuations in gene expression during the development of an organism.

Download full-text


Available from: Alexander van Oudenaarden
  • Source
    • "Degree of developmental stability: Mechanisms such as microguarding are expected to be important and efficient ways in which to carefully fine-tune developmental processes, ensuring the correct balance between developmental signals. Perturbations to these signals will disrupt normal development resulting in potentially significant fitness costs, selecting for any mechanisms that lower gene expression variation (Kim et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The regulation of gene expression is of fundamental importance to maintain organismal function and integrity and requires a multifaceted and highly ordered sequence of events. The cyclic nature of gene expression is known as 'transcription dynamics'. Disruption or perturbation of these dynamics can result in significant fitness costs arising from genome instability, accelerated ageing and disease. We review recent research that supports the idea that an important new role for small RNAs, particularly microRNAs (miRNAs), is in protecting the genome against short-term transcriptional fluctuations, in a process we term 'microguarding'. An additional emerging role for miRNAs is as 'micromessengers'—through alteration of gene expression in target cells to which they are trafficked within microvesicles. We describe the scant but emerging evidence that miRNAs can be moved between different cells, individuals and even species, to exert biologically significant responses. With these two new roles, miRNAs have the potential to protect against deleterious gene expression variation from perturbation and to themselves perturb the expression of genes in target cells. These interactions between cells will frequently be subject to conflicts of interest when they occur between unrelated cells that lack a coincidence of fitness interests. Hence, there is the potential for miRNAs to represent both a means to resolve conflicts of interest, as well as instigate them. We conclude by exploring this conflict hypothesis, by describing some of the initial evidence consistent with it and proposing new ideas for future research into this exciting topic.
    Full-text · Article · Sep 2015 · Heredity
  • Source
    • "Developmental timing is usually studied by means of direct observation of the animals at short time intervals using a dissecting microscope. Lethargus, cessation of pharyngeal pumping , ecdysis (Monsalve et al. 2011), and expression of GFP driven by promoters of genes that oscillate with the molts (Kim et al. 2013) have been used as hallmarks of the "
    [Show abstract] [Hide abstract]
    ABSTRACT: Caenorhabditis elegans postembryonic development consists of four discrete larval stages separated by molts. Typically, the speed of progression through these larval stages is investigated by visual inspection of the molting process. Here, we describe an automated method to monitor the timing of these discrete phases of C. elegans maturation, from the first larval stage through adulthood, using bioluminescence. The method was validated with a lin-42 mutant strain that shows delayed development relative to wild-type animals and with a daf-2 mutant that shows an extended second larval stage. This new method is inherently high-throughput and will finally allow dissecting the molecular machinery governing the speed of the developmental clock, so far hampered by the lack of a method suitable for genetic screens. Copyright © 2015, The Genetics Society of America.
    Preview · Article · Aug 2015 · Genetics
  • Source
    • "As developmental effects were very strong and affected many genes2334, we selected those genes that did not have a developmental effect (P < 0.05) or an effect which was opposite of what one would expect in a relatively slower developed bar-1(ga80) mutant (Supplemental figure C). We also selected on effect size (>0.5 or <−0.5) which resulted in 710 down- and 425 up-regulated genes compared to N2 (FDR = 0.05; Supplement Table 1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: C. elegans is extensively used to study the Wnt-pathway and most of the core-signalling components are known. Four β-catenins are important gene expression regulators in Wnt-signalling. One of these, bar-1, is part of the canonical Wnt-pathway. Together with Wnt effector pop-1, bar-1 forms a transcription activation complex which regulates the transcription of downstream genes. The effects of bar-1 loss-of-function mutations on many phenotypes have been studied well. However, the effects on global gene expression are unknown. Here we report the effects of a loss-of-function mutation bar-1(ga80). By analysing the transcriptome and developmental phenotyping we show that bar-1(ga80) impairs developmental timing. This developmental difference confounds the comparison of the gene expression profile between the mutant and the reference strain. When corrected for this difference it was possible to identify genes that were directly affected by the bar-1 mutation. We show that the Wnt-pathway itself is activated, as well as transcription factors elt-3, pqm-1, mdl-1 and pha-4 and their associated genes. The outcomes imply that this response compensates for the loss of functional bar-1. Altogether we show that bar-1 loss-of function leads to delayed development possibly caused by an induction of a stress response, reflected by daf-16 activated genes.
    Full-text · Article · May 2014 · Scientific Reports
Show more