Genome complexity: circular DNA in brains (Introduction)

by David Turell , Friday, August 11, 2017, 04:50 (2448 days ago) @ David Turell

It is not clear what they do:

https://phys.org/news/2017-08-circular-rna-linked-brain-function.html

"While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for?

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"RNA is much more than the mundane messenger between DNA and the protein it encodes. Indeed, there are several different kinds of non-coding RNA molecules. They can be long non-coding RNAs (lncRNAs) or short regulatory RNAs (miRs); they can interfere with protein production (siRNAs) or help make it possible (tRNAs). In the past 20 years, scientists have discovered some two dozen RNA varieties that form intricate networks within the molecular microcosm. The most enigmatic among them are circRNAs, an unusual class of RNAs whose heads are connected to their tails to form a covalently closed ring. These structures had for decades been dismissed as a rare, exotic RNA species. In fact, the opposite is true. Current RNA-sequencing analyses have revealed that they are a large class of RNA, which is highly expressed in brain tissues.

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"Intriguingly, most circular RNAs are unusually stable, floating in the cytoplasm for hours and even days on end. The systems biologists proposed that—at least sometimes - circRNAs serve gene regulation. Cdr1as, a large single-stranded RNA loop that is 1,500 nucleotides around, might act as a "sponge" for microRNAs. For example, it offers more than 70 binding sites for a microRNA called miR-7. MicroRNAs are short RNA molecules that typically bind to complementary sequences in messenger RNAs, thereby controlling the amounts of specific proteins produced by cells.

"Additionally, Rajewsky and his collaborators mined databases and discovered thousands of different circRNAs in nematode worms, mice and humans. Most of them were highly conserved throughout evolution. "We had found a parallel universe of unexplored RNAs," says Rajewsky. "Since publication the field has exploded; hundreds of new studies have been carried out."

"For the current paper in Science, the systems biologists teamed up with Carmen Birchmeier's lab at the MDC to reconsider Cdr1as. "This particular circle can be found in excitatory neurons but not in glial cells," says Monika Piwecka, one of the first authors of the paper and coordinator of most of the experiments. "In brain tissues of mice and humans, there are two microRNAs called miR-7 and miR-671 that bind to it." In a next step, Rajewsky and his collaborators selectively deleted the circRNA Cdr1as in mice using the genome editing technology CRISPR/Cas9. In these animals, the expression of most microRNAs in four studied brain regions remained unperturbed. However, miR-7 was downregulated and miR-671 upregulated. These changes were post-transcriptional, consistent with the idea that Cdr1as usually interacts with these microRNAs in the cytoplasm.

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"The changes in microRNA concentration had dramatic effects on the mRNA and proteins produced by nerve cells, especially for a group called "immediate early genes." They are part of the first wave of responses when stimuli are presented to neurons. Also affected were messenger RNAs that encode proteins involved in the maintenance of the animals' sleep-wake cycles.

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"'Functionally, our data suggest that Cdr1as and its direct interactions with microRNAs are important for sensorimotor gating and synaptic transmission," says Nikolaus Rajewsky. "More generally, since the brain is an organ with exceptionally high and diverse expression of circular RNAs, we believe that our data suggest the existence of a previously unknown layer of biological functions carried out by these circles.'"

Comment: the genome control gets more and more complex with more layers of control. It could be expected, as complex as the brain is, there are many layers of control over its plasticity.