Higher activity of TAGLN2 gene may drive PAH development: Study
Researchers call it a promising diagnostic and therapeutic candidate
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Higher TAGLN2 gene activity may contribute to the development of pulmonary arterial hypertension (PAH), according to a new study.
Using genetic analyses and experiments in animals, researchers identified two specific DNA sites that influenced TAGLN2 expression (activity) and PAH risk. These are two sites where a chemical mark called methylation is added to regulate gene activity. Methylation is part of a group of changes to gene activity that do not alter DNA itself, called epigenetics.
“Our findings delineate a novel epigenetic pathway in PAH pathogenesis [disease processes] and identify TAGLN2 as a promising candidate for future diagnostic and therapeutic strategies,” researchers wrote.
The study, “DNA Methylation-Mediated Regulation of TAGLN2 Expression Promotes Pulmonary Arterial Hypertension,” was published in Archives of Medical Research.
Epigenetics among processes implicated in PAH development
PAH is caused by the narrowing of pulmonary arteries, the small blood vessels that transport blood through the lungs, which restricts blood flow and makes it harder for the heart to pump blood through the lungs. This is driven by excessive growth of cells lining blood vessels, particularly pulmonary artery smooth muscle cells, leading to remodeling of blood vessels.
Epigenetics has been among the sets of biological processes implicated in PAH development and genetic predisposition to the disease. Another mechanism, called succinylation, is a modification that affects how proteins function inside cells and may influence inflammation, metabolism, and other processes.
“Given the established regulatory capacity of DNA methylation in transcriptional [gene activity] modulation, we hypothesize that this epigenetic mechanism may also influence the expression and function of succinylation-related genes … thereby contributing to the pathogenesis of PAH,” the scientists wrote.
TAGLN2 gene associated with PAH susceptibility
A team from China used advanced approaches to identify genes linked to disease. Genetic information on the Finnish population was obtained from the FinnGen database, which includes 301 European PAH patients and 345,634 healthy controls.
The team first analyzed multiple succinylation-related genes and identified three that are significantly associated with PAH risk: HAT1, PGAM1, and TAGLN2. While HAT1 appears to have a protective effect, reducing PAH risk, results suggested that both PGAM1 and TAGLN2 promote disease development.
Further analysis revealed that TAGLN2 was the only succinylation-related gene significantly associated with PAH susceptibility. Although the precise mechanisms through which TAGLN2 leads to PAH are not fully understood, the team noted that this gene is involved in processes important in PAH, including inflammation and smooth muscle contraction.
The researchers then identified two sites in DNA — cg13892570 and cg16107628 — where methylation was associated with lower TAGLN2 activity and, indirectly, the occurrence of PAH.
These findings provide novel insights into the pathogenesis of PAH, and highlight the role of epigenetic regulation in PAH. They also suggest potential clinical applications, such as the use of TAGLN2 as a biomarker or therapeutic target for the early diagnosis and treatment of PAH.
To validate these findings, the team conducted experiments in a rat model of PAH. Compared with healthy animals, PAH rats showed significantly increased pressure and thickening of the heart’s right ventricle, thickened arterial walls, and impaired right ventricular function.
Importantly, TAGLN2 activity was significantly elevated in lung tissue from the PAH rats, further supporting the gene’s role in disease progression.
The researchers noted that TAGLN2 appears to act as “a molecular link that integrates vascular smooth muscle contraction, immunometabolic signaling, and mitochondrial homeostasis [health].” They also highlighted the broader implications of the findings for patients and future research.
“These findings provide novel insights into the pathogenesis of PAH, and highlight the role of epigenetic regulation in PAH,” the team wrote. “They also suggest potential clinical applications, such as the use of TAGLN2 as a biomarker or therapeutic target for the early diagnosis and treatment of PAH.”
Among the study’s limitations, the scientists noted that future research should include more diverse patient groups. Exactly how succinylation and DNA methylation regulate TAGLN2 activity also needs further investigation. In addition, studies of other forms of pulmonary hypertension are warranted.
