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MicroRNAs Regulate the Noisy Genome

Summary and Discovery Science

Since the Human Genome Project, our knowledge of the genetic code has increased beyond that of simple genes. The genome is in fact quite complex, composed of overlapping gene regions, many stretches of repeating code, non-coding microRNAs (miRNAs), etc. In addition, despite every cell containing a complete copy of the genome, proteins are not identically expressed within different organs. There is inherent protein "noise" between different cell types. Noise in this case may be defined as variation in the concentration of a protein across different cel types. Hoffman and Pilpel (2015) summarize a research paper (Schmiedel et al., 2015) in which investigators were attempting to create a reporter method to measure fluctuations in protein noise. It has been suggested that miRNAs may have a regulatory role in filtering noise across different tissue types.

miRNAs are short pieces of non-coding RNA; they do not become translated to a protein product. Many miRNAs assume regulatory roles by binding to complementary sequence sites on mRNAs to decrease protein expression. If a miRNA targets an mRNA strand, the mRNA may be degraded, thus lowering the expression level of the gene that encoded the mRNA.
This paper explores a different kind of regulatory role for miRNAs.

This project was discovery science to try to determine how microRNAs may cooperate with mRNAs to regulate protein noise. Discovery science may be defined as those investigations without a defined hypothesis, often applying to large data-sets. In this case, investigators built a reporter model in order to understand if miRNAs regulated protein noise. They did not have a specific example in mind but were analyzing general trends.

Figure 1. When miRNAs are present, mRNA that is expressed at a lower level fluctuates less, but mRNA that is present in greater amounts shows more noise.
(Taken from Hoffman and Pilpel, 2015).

Genomic Methodology

In this project, investigators wondered whether organisms had evolved some sort of biological mechanism to control expression noise and attempted to attribute a regulatory role to miRNAs. They determined a model to quantify putative regulation on noise levels. The method consists of a transgenic fluorescence reporter that will measure gene expression noise, and enable researchers to modify whether that reporter has miRNA binding sites in the 3' untranslated region (3' UTR). Fluorescence under various states of miRNA binding sites was analyzed using flow cytometry and fluorescence activated cell sorting (FACS), and the data were incorporated into mathematical models. After modeling and completing their cell assays, the researchers concluded that miRNAs have a regulatory role in two different ways. For genes that are lowly expressed, miRNAs reduce protein noise, but for genes that are highly expressed, miRNAs increase noise (see Figure 1).

Take-Home Message

The biological phenomenon comes down to two forms of noise: intrinsic (within the cell, such as biochemical operations) or extrinsic (manifested in global differences between cells, such as ribosome copy number). Proteins expressed at low levels fall into the former category whereas highly expressed proteins are in the latter category. Extrinsic effects on protein expression would cause varied miRNA expression as well. For example, different cell types may have different numbers of RNA polymerases, affecting the number of active miRNA transcripts.

miRNA binding reduces intrinsic protein noise, but any increases in protein expression noise must be due to extrinsic noise that the miRNA cannot control. While this appears inconclusive, an analysis of the mouse genome revealed ~90% of genes could be regulated by miRNAs (Hoffman and Pilpel, 2015). The implications of this research include providing a mechanism by which cells reinforce their genomic identities by controlling unhealthy fluctuations in gene expression (noise) via miRNAs.


The investigators used a standard cell-assay reporter protocol to determine the effects of certain miRNA binding targets on protein expression levels. Their method was simple but elegant, and provided some insight into yet another layer of complexity regarding the genetic code. Not only does miRNA regulate the intrinsic levels of mRNAs, but it also reduces or increases protein noise based on cell type. The perspectives article successfully broke down the confusing differences between extrinsic and intrinsic noise, and provided examples of miRNA mechanisms in each case.

This project opens the doors to further research on miRNA regulation of specific proteins' noise levels. We now have technology to sequence the genome of individual cells. With a reporter system based on the one described in this paper, future scientists may understand the nuances between the genetic code of a cell, its transcriptome, and maybe even what makes specific genes noisier than others within a cell type.


Hoffman, Yonit and Pilpel Yitzhak. (2015) MicroRNAs silence the noisy genome. Science 348:41-42.

Schmiedel, Horn M. et al. (2015) MicroRNA control of protein expression noise. Science 348:128-132.

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