DSP Gene in COPD May Limit Ability of Lung Cells to Repair Injuries

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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DSP gene | COPD News Today | DNA illustration

Using the gene-editing technology CRISPR, a team led by scientists at Boston University has shown that several genes previously associated with susceptibility to chronic obstructive pulmonary disease (COPD) affect the development of lung cells.

The results specifically suggest that, in COPD, increased expression or activity of a gene called DSP might limit the ability of lung cells to repair injuries.

“Our hope is that this study will help in the understanding of the genetics of the disease, improve our understanding of how the disease occurs at a cellular level, and support the development of new therapies to treat these conditions,” Rhiannon Werder, MD, a postdoctoral fellow at the Center for Regenerative Medicine at Boston Medical Center and Boston University School of Medicine, and the study’s first author, said in a university press release.

These findings were detailed in a study titled “CRISPR interference interrogation of COPD GWAS genes reveals the functional significance of desmoplakin in iPSC-derived alveolar epithelial cells,” published in the journal Science Advances.

The causes of COPD are not fully understood, but increasing evidence suggests that genetics may play a role in influencing the disease’s development. Much of this evidence comes from genome-wide association studies, known as GWAS.

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Simplistically, GWAS look at the genetic codes of many people with or without a disease, and search for genetic variations that are disproportionately more common among those with a particular disorder. Such findings imply that the genetic variations uncovered confer susceptibility to developing that particular condition.

Prior GWAS analyses have identified dozens of genes associated with COPD susceptibility. However, the biological relevance of most of them is unclear.

Now, researchers used human stem cell lines to grow type 2 alveolar epithelial cells, referred to as iAT2s. These cells are progenitors in the alveoli — the tiny air sacs in the lungs where gas exchanges take place, and the main site of damage in the most severe form of COPD, emphysema.

The team then used a gene-editing technology called CRISPR to reduce the activity of nine genes that have been implicated in COPD susceptibility in prior GWAS studies.

“This is the first time that [CRISPR has] been applied in human induced pluripotent stem cells to understand the functional role of these genes,” said Andrew Wilson, MD, a pulmonologist at Boston Medical Center and associate professor of medicine at Boston University School of Medicine.

“It gets us closer to understanding how inherited factors help contribute to susceptibility to emphysema,” he said.

In a battery of cell experiments, the researchers demonstrated that reducing most of these genes’ activity levels led to an increase in markers of iAT2 maturation.

“These data suggest that multiple COPD-associated GWAS genes, including FAM13ADSPHHIPSOX4RBMS3, and ADGRG6, influence expression of genes central to AT2 maturation and function,” the team wrote.

Knocking down several genes — namely DSPTGFB2RBMS3, and ADGRG6 — also reduced the proliferation of iAT2s.

“Each of the genes we interrogated affected at least one iAT2 phenotype [trait] in our initial screen,” the researchers noted.

In subsequent experiments, researchers focused their attention on one of the nine genes, DSP, which had shown a strong effect on iAT2s in all of the earlier tests. GWAS data has indicated that increased DSP expression is linked to COPD risk.

The team showed that reducing DSP expression led to an increase in the activity of many genes known to be needed for normal iAT2 function. Lowering the activity level of the DSP gene also altered the cells’ metabolic profiles, and led to abnormalities in the physical interactions among neighboring iAT2s.

iAT2s with lowered DSP activity also showed a greater capacity for wound healing and less scarring, and less pronounced abnormalities after exposure to cigarette smoke.

“Together, our results suggest potential mechanisms through which DSP could contribute to the pathogenesis [development] of [COPD]. As increased DSP expression is associated with elevated risk for COPD, these could include decreases in AT2 proliferation and maturation following injury, leading to aberrant repair,” the researchers wrote.