MicroRNA control of protein expression noise

Schmiedel, Jörn M.; Klemm, Sandy; Yao, Zheng; Sahay, Apratim; Blüthgen, Nils; Marks, Debora S.; Oudenaarden, Alexander van

doi:10.1126/science.aaa1738

Cited by 370 publications

(418 citation statements)

References 40 publications

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“…Although earlier studies identified the stronger and more recognizable phenotypes of a few miRNAs (e.g., let-7), the majority of miRNAs exert subtle effects. It has been suggested that this is because miRNAs function to dampen noise arising from the stochastic nature of gene expression or raise the threshold required to elicit a response (Hornstein and Shomron 2006;Ebert and Sharp 2012;Ameres and Zamore 2013;Schmiedel et al 2015). This may explain why it has been so difficult to assign a clear-cut function to many miRNAs and why inactivation of a particular miRNA rarely gives rise to severe defects.…”

Section: Introductionmentioning

confidence: 99%

Novel regulation and functional interaction of polycistronic miRNAs

Truscott

Islam

Frolov

2015

RNA

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The importance of microRNAs in gene expression and disease is well recognized. However, what is less appreciated is that almost half of miRNA genes are organized in polycistronic clusters and are therefore coexpressed. The mir-11 998 cluster consists of two miRNAs, miR-11 and miR-998. Here, we describe a novel layer of regulation that links the processing and expression of miR-998 to the presence of the mir-11 gene. We show that the presence of miR-11 in the pri-miRNA is required for processing by Drosha, and deletion of mir-11 prevents the expression of miR-998. Replacing mir-11 with an unrelated miRNA rescued miR-998 expression in vivo and in vitro, as did expressing miR-998 from a shorter, more canonical miRNA scaffold. The embedded regulation of miR-998 is functionally important because unchecked miR-998 expression in the absence of miR-11 resulted in pleiotropic developmental defects. This novel regulation of expression of miRNAs within a cluster is not limited to the mir-11 998 cluster and, thus, likely reflects the more general cis-regulation of expression of individual miRNAs. Collectively, our results uncover a novel layer of regulation within miRNA clusters that tempers the functions of the individual miRNAs. Unlinking their expression has the potential to change the expression of multiple miRNA targets and shift a biological response.

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Section: Introductionmentioning

confidence: 99%

Novel regulation and functional interaction of polycistronic miRNAs

Truscott

Islam

Frolov

2015

RNA

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“…MicroRNA (miRNA), 3 small non-coding RNA sequences (ϳ22 nucleotides), have been heralded as regulators of gene expression that control postranscriptional mRNA stability or translation (4,5). miRNAs tune out transcriptional noise, allowing tighter control over protein expression of critical proteins defining a cell (6). Much like miRNA, glycosylation has the ability to exert global regulatory effects within the cell and its surroundings, and dysregulation can lead to biological disorders (7).…”

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confidence: 99%

MicroRNA-424 Predicts a Role for β-1,4 Branched Glycosylation in Cell Cycle Progression

Vaiana¹,

Kurćon

Mahal

2016

Journal of Biological Chemistry

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MicroRNA regulation of protein expression plays an important role in mediating many cellular processes, from cell proliferation to cell death. The human microRNA miR-424 is up-regulated in response to anti-proliferative cytokines, such as transforming growth factor ␤ (TGF␤), and directly represses cell cycle progression. Our laboratory recently established that microRNA can be used as a proxy to identify biological roles of glycosylation enzymes (glycogenes). Herein we identify MGAT4A, OGT, and GALNT13 as targets of miR-424. We demonstrate that MGAT4A, an N-acetylglucosaminyltransferase that installs the ␤-1,4 branch of N-glycans, is directly regulated by miR-424 in multiple mammary epithelial cell lines and observe the loss of MGAT4A in response to TGF␤, an inducer of miR-424. Knockdown of MGAT4A induces cell cycle arrest through decreasing CCND1 levels. MGAT4A does not affect levels of ␤-1,6 branched N-glycans, arguing that this effect is specific to ␤-1,4 branching and not due to gross changes in overall N-linked glycosylation. This work provides insight into the regulation of cell cycle progression by specific N-glycan branching patterns.

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“…The case F≃ 0 corresponds to the experimental situation reported in Ref. [26]. In this limit, I opt = 2.91 and I T F opt = 1.74.…”

Section: Summary and Discussionmentioning

confidence: 61%

“…The modelling of the post-transcriptional regulation is based on the mathematical models proposed in [25,26]. The models derive their strength from the fact that the theoretical results closely match the experimental observations in single cell measurements.…”

Section: Dynamics Of Two-gene and Fourgene Motifsmentioning

confidence: 99%

Functional characteristics of gene expression motifs with single and dual strategies of regulation

Pal

Ghosh

Bose

2016

Biomed. Phys. Eng. Express

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Transcriptional regulation by transcription factors and post-transcriptional regulation by microRNAs constitute two major modes of regulation of gene expression. While gene expression motifs incorporating solely transcriptional regulation are well investigated, the dynamics of motifs with dual strategies of regulation, i.e., both transcriptional and posttranscriptional regulation, have not been studied as extensively. In this paper, we probe the dynamics of a four-gene motif with dual strategies of regulation of gene expression. Some of the functional characteristics are compared with those of a two-gene motif, the genetic toggle, employing only transcriptional regulation. Both the motifs define positive feedback loops with the potential for bistability and hysteresis. The four-gene motif, contrary to the genetic toggle, is found to exhibit bistability even in the absence of cooperativity in the regulation of gene expression. The four-gene motif further exhibits a novel dynamical feature in which two regions of monostability with linear threshold response are separated by a region of bistability with digital response. Using the linear noise approximation (LNA), we further show that the coefficient of variation (a measure of noise), associated with the protein levels in the steady state, has a lower magnitude in the case of the four-gene motif as compared to the case of the genetic toggle. We next compare transcriptional with post-transcriptional regulation from an information theoretic perspective. We focus on two gene expression motifs, Motif 1 with transcriptional regulation and Motif 2 with post-transcriptional regulation. We show that amongst the two motifs, Motif 2 has a greater capacity for information transmission for an extended range of parameter values. * sghosh@kol.amity.edu † indrani@jcbose.ac.in

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MicroRNA control of protein expression noise

Cited by 370 publications

References 40 publications

Novel regulation and functional interaction of polycistronic miRNAs

Novel regulation and functional interaction of polycistronic miRNAs

MicroRNA-424 Predicts a Role for β-1,4 Branched Glycosylation in Cell Cycle Progression

Functional characteristics of gene expression motifs with single and dual strategies of regulation

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