Investigators have made a potentially exciting discovery by jumping into the abyss of the dark side of the genome. Once dismissed as "junk DNA," roughly 75 percent of the human genome do not code for proteins. But these dark regions of the genome are far from junk -- instead, they may hold tantalizing clues about disease states. A team of researchers recently plunged into these regions in search of clues about atherosclerosis -- a disease in which the arteries become increasingly hardened and narrow, obstructing blood flow and leading to heart disease. Using a preclinical model of atherosclerosis, the authors have uncovered a long, noncoding RNA (lncRNA) that may point the way toward new therapies for atherosclerosis and shed light on why the likelihood of the disease increases with age. Results are published in Science Translational Medicine.
"We have identified a new actor in controlling aging in the vessel wall and, surprisingly, it's not a traditional gene or protein. It's part of the non-coding genome. That was unexpected," said the senior author. "We know a lot about the importance of cholesterol and inflammation in heart disease, but this is a new, additional pathway. We need to think carefully about how it might impact the development of therapeutics for cardiovascular disease."
The authors used a mouse model of atherosclerosis in which mice begin to develop atherosclerotic lesions at 12 weeks. The investigators isolated RNA from the inner-most lining of the blood vessel wall and looked across the entire genome at all RNAs, searching for which ones had changes in activity during disease progression or regression. One of the most dynamic was SNHG12, a long stretch of RNA that does not code for a protein but is found across multiple species, including humans, pigs and mice.
To better understand SNHG12's role, the researchers conducted experiments in which they either knocked down its activity or ramped it up. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr−/− miceby increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis.
To understand what SNHG12 was doing, the team looked for who its partners were. LncRNA pulldown in combination with liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Without these partners working together, vessel walls became leaky and permeable to bad cholesterol.
The team could reverse this phenomenon by adding a small molecule that promotes DNA damage repair, suggesting a potential therapeutic avenue to pursue. The anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown.
SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers.
"What's really exciting is that RNA therapeutics -- in which we deliver RNA molecules or small molecules that can help regulate RNA -- is a growing area," said the senior author. "Our work help lays a foundation for pursuing these kinds of therapies for atherosclerosis."
https://stm.sciencemag.org/content/12/531/eaaw1868
A long, noncoding RNA (lncRNA) links atherosclerosis and aging
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