Genome complexity: expanding RNA population (Introduction)

by David Turell , Friday, April 05, 2024, 16:19 (24 days ago) @ David Turell

New RNA functional forms found:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/05_april_2024/41859...

"A plethora of new types of noncoding RNAs have been discovered, including thousands of long noncoding RNAs (lncRNAs), many of which have no identified functions. Throughout this “RNA revolution,” one property of RNA has been thought to be constant: RNAs are shortlived molecules that turn over, unlike DNA, which is much more stable. On page 53 of this issue, Zocher et al. challenge that paradigm by showing that newly synthesized RNA labeled with 5-ethynyl uridine (EU) in early postnatal mice was still present in many brain cells 2 years later. The complex pattern of when and which cells are labeled suggests that EU that is incorporated into RNA in neural progenitor cells (NPCs) frequently remains in adult neurons. This suggests that a diversity of long and repeat-rich RNAs, collectively called long-lived RNAs (LL-RNAs), can be stable fixtures in postmitotic and quiescent neural cells.

"There have been decades of studies that demonstrate that the half-lives of mRNA range from minutes to hours, with relatively “stable” ribosomal RNA persisting for days. So how could LL-RNAs not have been found before? A key difference is that Zocher et al. examined RNA in mouse brains filled with postmitotic neurons, whereas most studies have examined proliferative cells. The prior studies show that RNA turnover is dynamically regulated to meet cellular demands. Thus, because RNAs are not subject to unrestrained ribonucleases (RNases), if they are structurally protected in nuclei, perhaps they can persist indefinitely.

"An important point is that the persistent EU label observed by Zocher et al. is distinctly nuclear. Why would this be, particularly because RNAs for protein production are in the cytoplasm? Answers to this question will require future research, but the authors provide one possibility focused on satellite RNAs, which are expressed from small tandem satellite repeats that form peri- and centromeric heterochromatin. Several studies have shown that brief transient satellite RNA expression in cycling cells plays a role in peri- and centromere structure in chromosomes. Zocher et al. report that satellite RNA is enriched in LL-RNAs and further suggest that it continually serves to maintain repressive chromatin modifications, particularly histone H3 lysine 27 (H3K27) methylation, on centromeric heterochromatin.

***

"Stable RNAs, potentially analogous to LL-RNAs, may have been found before. Evidence of long-lived structural RNAs in the nuclei of human cells was reported in 2014. The highly repetitive “junk” RNA of the genome, called CoT-1 RNA, was detected in human cells by in situ hybridization. CoT-1 RNA labeled euchromatin, not heterochromatin, and had unusual properties. CoT-1 RNA tightly localized in cis to the chromosome territory (unlike mRNAs), and the bright RNA territory remained unperturbed for 16 to 32 hours after transcriptional inhibition. Although there are caveats to the use of transcriptional inhibitors, the results suggested that CoT-1 RNA may be part of a protein-RNA nuclear scaffold (also known as the matrix), the existence of which was reported in earlier studies, although these results were debated.

"Recently, a more-selective procedure was developed to isolate highly insoluble nuclear RNAs that remain after robust extraction and deoxyribonuclease (DNAse) digestion and that cofractionate with architectural RNAs [X-inactive specific transcript (XIST) and nuclear paraspeckle assembly transcript 1 (NEAT1)], which have established roles in forming nuclear structures. The 15% of insoluble scaffold RNAs (scaffRNAs) that remained with XIST and NEAT1 RNAs were CoT-1 RNAs. Sequencing showed that scaffRNAs were largely long and repeatrich, primarily intron-rich pre-mRNAs, lncRNAs, and intergenic transcripts. There are strong similarities between these scaffRNAs and the EU-labeled LL-RNAs found by Zocher et al. Potentially relevant to LLRNA functions, the removal of scaffRNAs, by numerous different means, rapidly resulted in condensation of euchromatin and delocalized specific nuclear matrix proteins, which other studies further support regulate chromatin packaging."

Comment: sorry for the density of this summary article, which points out that RNA's are the workhorses of the genome. The known population of RNA's is now enormous. Which leads to the next obvious point: such complexity demands design.