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No Mere Bike Messenger, RNA Code Surpassing DNA in Complexity

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The concept of a “DNA Code” has a long pedigree in genetics. But what about the other nucleic acids — the RNAs that use ribose instead of deoxyribose? Are they just simple conveyors of the library of genetic information in DNA, a humble bicycle messenger of the cell? Or do they have their own code? Last month, Nature published a Technology Feature by Kelly Rae Chi with an intriguing title, “The RNA code comes into focus.”

Chi begins with the m6am RNA modification we first mentioned in January, but doesn’t end there. Modifications to RNA bases are turning up all over, and their functions are just beginning to be understood. A feel for the importance of these new findings can be had by following the money:

In the past few years, He’s group has discovered evidence suggesting that RNA modifications provide a way to regulate transcripts involved in broad cellular roles, such as switching on cell-differentiation programs. Researchers need better technologies to explore these links; and, in October 2016, the US National Institutes of Health awarded He and Pan a 5-year, US$10.6-million grant to establish a centre to develop methods for identifying and mapping RNA modifications. [Emphasis added.]

On March 2, Japan’s RIKEN lab issued a news item stating, “Improved gene expression atlas shows that many human long non-coding RNAs may actually be functional.” RIKEN’s FANTOM Consortium is constructing a map of human non-coding RNAs. The latest findings calls to mind the surprises with DNA under ENCODE, but this time with RNA under FANTOM:

The atlas, which contains 27,919 long non-coding RNAs, summarizes for the first time their expression patterns across the major human cell types and tissues. By intersecting this atlas with genomic and genetic data, their results suggest that 19,175 of these RNAs may be functional, hinting that there could be as many — or even more — functional non-coding RNAs than the approximately 20,000 protein-coding genes in the human genome.

The atlas, published by Nature on March 9, expands into the RNA sphere from findings in the ENCODE and GENCODE databases. As with ENCODE, scientists so far are cataloging expression profiles without necessarily understanding actual functions. Presumably, though, cells have reasons for expressing these long non-coding RNAs (lncRNAs). The search for the actual functions is poised to bear fruit, as it did with ENCODE.

On the same day (March 9), Nature published another article finding “More uses for genomic junk.” Karen Adelman and Emily Egan point out that previous studies may have missed the functions of “junk DNA” by overlooking the key:

In addition to protein-coding messenger RNAs, our cells produce a plethora of diverse non-coding RNA molecules. Many of these are generated from sequences that are distant from genes, and include regulatory DNA sequences called enhancers. Transcription factors bound at enhancers are thought to regulate gene expression by looping towards genes in 3D space. The potential functions of non-coding enhancer RNAs (eRNAs) in this process have been avidly debated, but there has been a tendency to write them off as accidentally transcribed by-products of enhancer–gene interactions. After all, how could short, unstable, heterogeneous RNAs have a role in gene regulation? Writing in Cell, Bose et al. reveal that these eRNAs can indeed be functional, when produced in proximity to the enzyme CBP.

And what does the enzyme CBP do?

One transcriptional co-activator is the acetyltransferase enzyme CBP, which, along with its close relative p300, associates with DNA in enhancer regions, where it adds acetyl groups to histones and transcription factors. This acetylation promotes the recruitment of numerous transcriptional co-activators and chromatin-remodelling proteins that have acetyl-binding regions, along with the RNA-synthesizing enzyme polymerase II (Pol II).

In other words, CBP (a protein enzyme) and enhancer RNAs need to be together to work. The implication is clear; far from being accidental by-products, eRNAs are functional. They are involved in making genes accessible to the translation machinery, and regulating their expression. Transcription, long thought to be the engine, is just part of a much more complex factory.

A model is emerging in which transcription is itself an early step in enhancer activation. Pol II is recruited by transcription factors and maintains opens chromatin. Once the enzyme begins to transcribe, the nascent eRNA it produces stimulates co-activator proteins such as CBP in the region in a sequence- and stability-independent manner. The activities of these proteins promote the recruitment of more transcription factors, Pol II and chromatin-remodelling proteins, enabling full enhancer activation. In addition, Pol II itself can serve as a vehicle for attracting chromatin-modifying enzymes that spread more molecular marks associated with chromatin activation across the transcribed region. In this manner, transcription of enhancers can generate a positive-feedback loop that stabilizes both enhancer activity and gene-expression profiles.

Overall, the current study fundamentally changes the discourse around eRNA functions, by demonstrating that these RNAs can have major, locus-specific roles in enhancer activity that do not require a particular RNA-sequence context or abundance. Furthermore, by providing strong evidence that CBP interacts with eRNAs as they are being transcribed, this study highlights the value of investigating nascent RNAs for understanding enhancer activity.

Speaking of 3D space, researchers at the Max Delbrück Center for Molecular Medicine (MDC) have been producing a 3D map of the genome, underscoring the complex dance of DNA, RNA, and proteins:

Cells face a daunting task. They have to neatly pack a several meter-long thread of genetic material into a nucleus that measures only five micrometers across. This origami creates spatial interactions between genes and their switches, which can affect human health and disease. Now, an international team of scientists has devised a powerful new technique that ‘maps’ this three-dimensional geography of the entire genome. Their paper is published in Nature.

The paper explains the Genome Architecture Mapping (GAM) technique they created and how it elucidates the interactions between genes and their enhancers.

GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei.

Isn’t that a worthy function? Keeping the genome organized is not a role that ‘genetic junk’ is likely to succeed at.

Another clue to function in RNA comes from a finding announced by Science Daily, “Start codons in DNA may be more numerous than previously thought.” When DNA needs to be translated into messenger RNA (mRNA), it was thought that a ‘start codon’ identified the start of the gene, and that there were only seven of these in the genetic code. But nobody had ever checked, this article says. Scientists from the National Institute of Standards and Technology found, to their surprise, that there are “at least 47 possible start codons, each of which can instruct a cell to begin protein synthesis.” Indeed, “It could be that all codons could be start codons.” The possibilities this opens up for expanding the complexity of RNA transcripts can only be imagined at this point.

We’ll end with one more example of the revolution in RNA functions. Scientists at Indiana University and colleagues found an example of “Hybrid incompatibility caused by an epiallele.” The open-access study, published in PNAS, “demonstrates a case of epigenetic gene silencing rather than pseudogene creation by mutation” in the lab plant Arabidopsis. Here’s a case where the RNA tail seems to wag the DNA dog:

Multicopy transgenes frequently become methylated and silenced, particularly when inserted into the genome as inverted repeats that can give rise to double-stranded RNAs. Such double-stranded RNAs can be diced into small interfering RNAs (siRNAs) that guide the cytosine methylation of homologous DNA sequences, a process known as RNA-directed DNA methylation (RdDM)…. This interesting case study has shown that naturally occurring RdDM, involving a new paralog that inactivates the ancestral paralog in trans, can be a cause of hybrid incompatibility.

Bypassing genetic mutations and natural selection, this “previously unrecognized epigenetic phenomenon” might help explain cases of apparently rapid speciation by a non-Darwinian process. We’ll leave that possibility for others to investigate.

In short, RNA has graduated from servant to master. The numerous RNA transcripts floating around in the nucleus, once thought to be genetic “noise,” may actually be the performance, like virtuosos in an orchestra bringing static notes written in DNA to life. This huge shift in thinking appears to be deeply problematic for neo-Darwinism. It sounds like a symphony of intelligent design.

Photo: Bicycle messenger, by Anneli Salo (Own work) [CC BY-SA 3.0], via Wikimedia Commons.