Since the discovery of DNA structure in the 1950s, the central dogma of molecular biology has been widely accepted in the scientific community. Essentially, the central dogma holds that information flows from DNA to RNA to protein (Figure 1). DNA is a molecule inside the cell nucleus that stores genetic information in chemical form. This genetic information determines traits such as hair color, height or susceptibility to a disease. For a trait to be expressed, this genetic information has to be transferred to proteins, molecules that serve both structural and functional roles in cells. For example, the growth hormones that help teenagers grow taller during puberty are proteins. The final player of the central dogma, messenger RNA (mRNA), serves the function of relaying information from DNA to protein. RNAs are molecules that have some similarity to DNA in structure and chemical composition. Because they carry the code for making proteins, mRNAs are also called “coding RNAs”. Traditionally, it was thought that the majority of RNAs in our cells are mRNAs. However, recent studies have called this into question, suggesting instead that most RNAs do not code for proteins, and these non-coding RNAs might even hold the key to furthering our understanding of mammalian physiology and diseases.

Figure 1.  The central dogma of biology describes the flow of genetic information from DNA to RNA to proteins. Transcription is the transfer of genetic code from DNA to RNA and takes place in the nucleus. RNAs then exit the nucleus into the cell body. mRNAs undergo translation in the cell body, which is the making of protein based on the code in the mRNA. However, there are RNAs that do not code for proteins, such as lncRNAs. 

A new class of RNA

There are multiple types of non-coding RNAs that perform different functions in our cells (You can learn more about types of non-coding RNA in this article: http://www.nature.com/scitable/topicpage/rna-functions-352 ). Recently, a new class of non-coding RNAs, called long noncoding RNAs (lncRNAs), has been described.

LncRNAs are defined as noncoding RNAs that are larger than 200 nucleotides in size (nucleotides are molecular subunits that make up both DNA and RNA)[1]. Only a few well-characterized examples of lncRNAs currently exist in the literature, but some computational biologists predict that there may be 8,000 of them or more encoded in the human genome [2,3]. As a comparison, there are approximately 23,000 mRNAs [1,4]. LncRNAs are present in cells in lower amounts than their mRNA counterparts, and are more tissue or cell-type specific [2]. That means some of them can only be found in one type of tissue or cell in the body, for example, a particular kind of brain cell, but not elsewhere. This high specificity indicates that they may serve important functions in the development of certain tissues, and they may be useful biomarkers for identifying cell types in the body.

What are lncRNAs doing?

The existence of lncRNAs as a new class of RNA is not universally accepted among biologists. Some believe that they may just be junk produced during the process of making mRNAs. One issue fueling the controversy is how much lncRNAs have changed during evolution when compared to mRNAs. Just as there are classes of organisms that evolved from the same ancestor and thus look similar (think about closely related mammals such as dogs and wolves), there are traits on a molecular level that look the same as well. Many mammals have a similar set of proteins, and protein A from a mouse may very closely resemble protein A from a human. This concept is called evolutionary conservation. Biologists use evolutionary conservation as a sign of important function because nature usually abides by the rule “if it’s not broken, don’t fix it.” If a particular RNA is extremely important to the ability of an organism to live and reproduce, it will remain relatively unchanged across a wide variety of species. However, lncRNAs have not been as well conserved over the course of evolution as mRNAs [5]. This causes some scientists to believe that lncRNAs may not be performing important biological functions but are just cellular byproducts.

One of the strongest arguments in favor of lncRNA function is that many lncRNAs are associated with disease processes. For example, a lncRNA called ANRIL is expressed in prostate cancer, and may be responsible for cancer initiation [6]. ANRIL is also associated with increased risk of heart diseases [2,7]. Another lncRNA, HOTAIR, is expressed in metastatic breast cancer (breast cancer that is capable of spreading to other organs in the body) [8]. lncRNAs could be important biomarkers to help doctors understand what steps are necessary to treat the disease, especially when they are correlated with disease processes such as cancer metastasis.

The future of lncRNA research

Since the field of lncRNA research is very new, little is known about exactly how these RNAs function in the cell. Initial investigations into lncRNA functions have relied heavily on experiments to reduce expression levels of a candidate lncRNA in cell cultures and study any defects this may produce. One such study published in early 2013 demonstrated that artificially decreasing the amount of a lncRNA called TINCR resulted in improper skin differentiation, meaning that skin cells failed to create the essential airtight barrier of the skin layers, which is an important first defense against infection and dehydration[9]. The smoking gun which would prove lncRNA functional relevance would be an experiment that shows how a certain disease does not occur in the absence of a vital lncRNA, but that turning on that lncRNA actually causes initiation of the disease.

LncRNAs represent a large and relatively unstudied addition to the field of molecular biology. Much like discovering a new color or method for mixing paints, these recently discovered molecules might help biologists create a far more detailed and accurate picture of cell and animal physiology. We may sit on the verge of an RNA renaissance that could revolutionize our current understanding of biology and lead to unprecedented breakthroughs in regenerative medicine as well as our ability to detect and treat disease.

Abbie Groff is a graduate student in Systems Biology Ph.D. program at Harvard University

References

[1] What are lncRNAs? http://www.exiqon.com/lncrna
[2] Cabili MN, et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011. 25(18):1915-27.
[3] Human LincRNA Catalog. http://www.broadinstitute.org/genome_bio/human_lincrnas/
[4] What is the human genome and how big is it?http://www.edinformatics.com/math_science/human_genome.htm
[5] Pang KC, et al. Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends Genet. 2006. 22(1): 1-5.
[6] Yap KL et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010. 38(5): 662-74.
[7] Pasmant E, et al. ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB. 2011. 25(2) 444-448.
[8] Saey, Tina H. Missing Lincs: Lesser-known genetic material helps explain why humans are human. 2011. Science News. https://www.sciencenews.org/article/missing-lincs
[9] Conger, Krista. Researchers discover master regulator of skin development. 2012. http://med.stanford.edu/ism/2012/december/khavari.html

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