DNA changes in lungs may influence disease risk in IPF: Study
Researchers investigate impact of genetic modifications
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Abnormalities in DNA methylation — a type of genetic modification that can alter the activity of a gene without changing its sequence — may affect a person’s risk of developing idiopathic pulmonary fibrosis (IPF), according to a new study.
The researchers say this work has uncovered “novel roles” for certain genes in IPF pathogenesis, which describes how a disease begins, progresses, and is maintained within the body.
“These findings enhance our understanding of the associations between DNA methylation and IPF risk, and suggest novel targets for preventive and therapeutic interventions,” the scientists wrote.
The study, “Epigenome-wide Mendelian randomization with multi-omics validation identifies epigenetic drivers of idiopathic pulmonary fibrosis,” was published in the journal Communications Biology.
IPF is a disorder marked by fibrosis, or scarring, in the lungs. The underlying biological mechanisms that drive fibrosis in IPF are not fully understood, though several risk factors have been identified.
Going beyond the genetic code to investigate disease risk in IPF
Previous studies have suggested that certain genetic variants may increase the risk of IPF. But these studies have generally focused on the genetic code itself, and that isn’t the only way that genes in cells can be altered. Another way to change genes’ activity is through a process called methylation, the researchers noted.
With methylation, a small molecular motif, called a methyl group, is attached to DNA molecules at specific sites. If a person’s genetic code is imagined as the words printed in a book, methylation is sort of like notes scribbled in the margins — it doesn’t alter the code itself, but it can profoundly affect which genes are active or not by modulating the activity of transcription factors, which are the proteins responsible for turning genes on or off.
In this study, a team of scientists in China set out to identify whether methylation changes in certain genes may affect IPF risk. To that end, the researchers used established datasets and performed a type of analysis called Mendelian randomization. Essentially, this analysis looked for abnormal methylation patterns that were consistently associated with genetic changes linked with IPF risk.
The analysis identified 13 methylation sites predicted to influence IPF risk. Upon further validation, the researchers zeroed in on methylation regions in two specific genes, called MAN2A2 and TRIM27. Available data indicated that the activity of both of these genes varied in accordance with methylation patterns, and among IPF patients the activity of these genes was correlated with measures of lung function.
The researchers noted that, in analyses looking only at the genetic code, no association was seen between genetic factors regulating MAN2A2 or TRIM27 activity and IPF risk. This suggests “that the roles of these two genes in IPF are more likely driven by DNA methylation alterations rather than genetically regulated expression changes,” the scientists wrote.
These novel signatures could serve as promising prevention and treatment targets for IPF.
In further tests, the researchers found that abnormal methylation of the MAN2A2 gene in IPF means that a specific transcription factor called ZNF384 is not able to properly regulate the gene. Their data indicate that the lack of ZNF384 binding leads to abnormally low activity of the MAN2A2 gene, which in turn contributes to fibrosis.
“These novel signatures could serve as promising prevention and treatment targets for IPF,” the scientists wrote, calling for further studies to validate and expand upon these findings.
