Researchers identify quartet of genes that may drive idiopathic PAH
Scientists combine computational analysis, lab models to find potential targets
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A team of scientists in China identified four genes that may serve as potential treatment targets for idiopathic pulmonary arterial hypertension (PAH).
“This study combined [computer-based genetic sequencing] analyses with experimental validation [in cell and animal models] to identify COL1A1, MYL9, COL1A2, and TPM2 as potential key driver genes in [idiopathic] PAH,” the researchers wrote.
The study, “Identification of key driver genes in idiopathic pulmonary arterial hypertension by single-cell RNA sequencing and experimental validation,” was published in Biochemical and Biophysical Research Communications.
PAH is marked by the abnormal growth of cells in the walls of blood vessels that carry blood from the heart to the lungs. This causes blood vessels to narrow, raising blood pressure and straining the heart. In idiopathic PAH, the disease’s underlying cause is not known.
The scientists wanted to better understand the factors driving the abnormal growth of these cells, called pulmonary artery smooth muscle cells (PASMCs), in idiopathic PAH.
Algorithms point to genes with abnormal expression
They started their analysis by using a sophisticated set of computer algorithms to analyze publicly available gene expression datasets. Gene expression refers to the extent to which individual genes are turned on or off. The researchers were looking for genes that are substantially more active when PASMCs are growing abnormally, as they do in PAH. In particular, they were trying to identify the so-called hub genes.
Gene expression datasets are inherently complex, because, within a cell, the activity of all genes is interconnected. So if one disease-driving gene changes its activity, several other genes will also shift their expression in response. Hub genes are the key genes that are connected and influence the activity of many other genes within a dataset.
The analysis revealed dozens of genes with abnormal expression in cells from people with idiopathic PAH, and the researchers zeroed in on four hub genes: COL1A1, MYL9, COL1A2, and TPM2.
They then conducted tests in lab models to verify their computer-based analyses. In a rat model of PAH, they confirmed that the activity of these four genes was abnormally high in PASMCs. Cell experiments also showed that knocking down the activity of each of these genes helped slow abnormal PASMC growth.
“These findings provide novel insights into the molecular mechanisms of [idiopathic] PAH and highlight these hub genes as potential therapeutic targets,” the researchers wrote, noting that further studies will be needed to validate their results.
