Researchers report that a small RNA called tsRNA-Glu-CTC plays a major role in controlling cholesterol production and may influence the development of heart disease. The work used PANDORA-seq, a sequencing method developed at UC Riverside, to reveal previously hidden small RNAs in the liver, the organ central to cholesterol metabolism. In the mouse samples the team found tsRNA-Glu-CTC to be highly abundant, accounting for more than 65% of detectable tRNA-derived small RNAs.
The study established a direct link between tsRNA-Glu-CTC and SREBP2 (Sterol Regulatory Element-Binding Protein 2), a master regulator of cholesterol synthesis. According to the lead author, higher tsRNA-Glu-CTC boosts SREBP2 activity and activates the genes that make cholesterol. This mechanism contributes to higher cholesterol levels and raises the risk of atherosclerosis, the slow buildup of sticky plaque in arteries; approximately 50% of Americans aged 45 to 84 live with undiagnosed atherosclerosis, the authors note.
In mice, an antisense oligonucleotide (ASO) designed to block tsRNA-Glu-CTC lowered cholesterol and produced less severe atherosclerosis. The team also found that a naturally occurring, chemically modified form of the RNA was more effective at regulating cholesterol than synthetic versions, a result that could guide future targeted drugs. Human blood analyses showed that people with elevated tsRNA-Glu-CTC tended to have higher circulating cholesterol. Additional contributors came from several other universities, and the work was partially funded by National Institutes of Health grants.
Difficult words
- sequence — method to determine the order of genetic basessequencing
- abundant — present in large amounts or numbers
- regulator — a molecule that controls a biological process
- antisense oligonucleotide — short strand of synthetic nucleic acid
- modify — to change a molecule's chemical structure or propertiesmodified
- circulate — to move or flow through a systemcirculating
- atherosclerosis — disease with fatty plaque buildup in arteries
- metabolism — chemical processes that keep a living body functioning
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Discussion questions
- How might the link between tsRNA-Glu-CTC and SREBP2 change approaches to treating high cholesterol?
- What are the advantages and possible concerns of using chemically modified natural RNAs instead of synthetic versions for drugs?
- How does a sequencing method like PANDORA-seq change what researchers can discover about diseases?
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