Scientists have identified a gene that may play a protective role in preventing heart disease. Their research revealed that the gene, called MeXis, acts within key cells inside clogged arteries to help remove excess cholesterol from blood vessels.
Published in the journal Nature Medicine, the study in mice found that MeXis controls the expression of a protein that pumps cholesterol out of cells in the artery wall.
MeXis is an example of a "selfish" gene, one that is presumed to have no function because it does not make a protein product. However, recent studies have suggested that these so-called "unhelpful" genes can actually perform important biological functions without making proteins and instead producing a special class of molecules called long non-coding RNAs, or lncRNAs.
"What this study tells us is that lncRNAs are important for the inner workings of cells involved in the development of heart disease," said senior author of the study. "Considering many genes like MeXis have completely unknown functions, our study suggests that further exploring how other long non-coding RNAs act will lead to exciting insights into both normal physiology and disease."
In the study, researchers found that mice lacking MeXis had almost twice as many blockages in their blood vessels compared to mice with normal MeXis levels. In addition, boosting MeXis levels made cells more effective at removing excess cholesterol.
Authors identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner.
Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17.
In the next phase of the study, researchers will further explore how MeXis affects the function of cells in the artery wall and will test various approaches to altering MeXis activity. The researchers are interested in finding out if MeXis could be targeted for therapy of cardiovascular disease.
"The idea that lncRNAs are directly involved in very common ailments such as plaque buildup within arteries offers new ways of thinking about how to treat and diagnose heart disease," said the study's lead author. "There is likely a good reason why genes that make RNAs rather than proteins exist. A key question for us moving forward is how they may be involved in health and disease."
Long non-coding RNAs role in heart disease
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