RNA Editing Makes Humans Complex

Humans are able to achieve greater biological complexity due to RNA editing, according to research by scientists in Singapore and the US.

AsianScientist (Oct. 27, 2017) – In a study published in Nature, researchers in Singapore and the US have discovered how humans achieve higher developmental and cognitive complexity despite having approximately the same number of protein-coding genes as other living organisms.

The genome contains all the necessary information that dictates cellular and organismal behavior. Given the developmental and cognitive complexity of humans, one would have thought that our genome would contain many more protein-coding genes than most other living organisms.

Surprisingly, however, the Human Genome Project has uncovered only approximately 20,000 protein-coding genes in our genome, a number not much different from other mammals, vertebrates, flies, or even worms. Part of the answer to this apparent paradox lies in the complex processing of RNA after it has been transcribed from the genome.

RNA editing provides a powerful method to diversify the pool of RNAs available, allowing the fine-tuning of biological function. Adenosine-to-inosine (A-to-I) editing is the most common kind of editing in animals, and over a million A-to-I editing sites are present in the human transcriptome. However, the extent to which each site is edited in different biological contexts is largely unknown.

In this study, a team led by Professor Tan Meng How of the Genome Institute of Singapore (GIS) has comprehensively profiled A-to-I editing in multiple human tissues and compared editing in humans to non-human primates and mice. Since there are only two catalytically active A-to-I editing enzymes (called ADARs) in humans, which cannot account for the diverse spatiotemporal patterns of editing, Tan’s team computationally predicted potential new regulators of editing.

They examined one novel regulator, AIMP2, in greater detail and found that it promotes the degradation of the ADAR proteins and plays an important role in controlling editing levels in muscles.

For decades, RNA editing was believed to occur predominantly in neuronal cell types. Subsequently, studies leveraging next-generation sequencing technologies started to reveal that editing may play important roles in other non-brain tissues, although these studies were limited in comprehensiveness.

The team at GIS first found that in humans, the highest amount of editing in protein-coding regions occurs in the artery, and not the brain. Secondly, from their cross-species analysis, they discovered that in terms of editing profiles, the human brain is more similar to the human lung than to the mouse brain or even the chimpanzee brain.

The researchers also debunked the long-held belief that an editing site is a target of either the ADAR1 or the ADAR2 enzyme, and that this dependence is invariable between tissues. Instead, they revealed that site-specific editing by ADAR1 or ADAR2 is context dependent and can vary greatly between tissues.

“Although there are about a dozen groups working on similar research, our research stands out in that we make effective use of new technologies together with traditional molecular biology, cell biology, genetics, and biochemistry techniques. We also focus on Asia-specific diseases and collaborate with local clinicians,” said Tan.

“Collectively, our paper serves as a useful resource for the scientific community and lays the foundation for future studies into the functions and regulation of RNA editing,” he added.

“This is a truly significant jump in the understanding of RNA editing and functionality,” said Executive Director of GIS, Professor Ng Huck Hui. “It is an important stepping stone for scientists to learn more about what makes us human, and from there, how we can look to RNA editing to improve human health.”

The article can be found at: Tan et al. (2017) Dynamic Landscape and Regulation of RNA Editing in Mammals.


Source: A*STAR; Photo: Shutterstock.
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