Epigenetic regulator promotes immunopathogenesis in COPD

In chronic obstructive pulmonary disease, COPD, complex inflammatory processes, and injury to the lung tissue (emphysema) ultimately cause lung alveolar epithelial cells to die. An increased number of inflammatory macrophages differentiating from blood monocytes is largely responsible for this.

Lung Health and Immunity (LHI) researchers around Thomas Conlon, Aicha Jeridi and Gizem Günes from the Yildirim lab in collaboration with researchers from the Schneider lab at the Institute of Functional Epigenetics (IFE) have now discovered: An epigenetic factor in the form of an enzyme decisively influences the recruitment of these inflammatory macrophages to the lung and thus the progression of the disease. Conversely, inhibiting this factor could offer therapeutic potential in monocyte-related inflammation. This is valuable because the exact molecular mechanisms involved in the development and progression of COPD are still unclear.

“We were wondering why only a certain percentage of smokers develop COPD, and why the course of disease progression are so different from patient to patient,” said the study lead Ali Önder Yildirim, director at the institute of Lung Health and Immunity. The LHI researchers have taken a closer look at what happens in the immunological processes triggered by monocytes: they discovered that the enzyme PRMT7 (protein arginine methyltransferase) is elevated in lung tissue and localized to macrophages in patients with COPD. This marked enrichment correlates and sensitizes alveolar cells towards ferroptotic cell death and thus the severity of the disease. Importantly, the reduced expression of PRMT7 in COPD mouse models protects against the development of the disease. Thus, targeting epigenetic regulation by arginine methylation offers preventive as well as therapeutic potential in inflammation triggered by monocyte recruitment.

Background on the underlying epigenetic regulation by PRMT7:

DNA in the cell nucleus is wrapped in the smallest "packaging unit" around a core of proteins, the histones. The ends of the histone strands protrude from this "packaging unit" and are the target of histone-modifying enzymes – including methylation. Protein-arginine modifications/methylations - such as those caused by PRMT7 - are particularly well known. These modifications are not genetic mutations, the genetic information in the genome remains unchanged, but have the ability to regulate gene expression. 

In this case, methylation by the enzyme PRMT7 triggers an epigenetic modification to the histones. This in turn causes the disease-promoting accumulation of monocyte-derived proinflammatory macrophages.

Original publication:

Günes Günsel et al. (2022). The Arginine Methyltransferase PRMT7 Promotes Extravasation of Monocytes resulting in tissue injury in COPD. Nat Comm. DOI: 10.1038/s41467-022-28809-4.