This insight provides a potential target for intervention in pulmonary diseases.
As our lungs develop, tiny air sacs (or alveoli) that facilitate the exchange of oxygen and carbon dioxide when we breathe are formed in a process known as alveologenesis. Abnormal alveologenesis has damaging effects and has been associated with chronic lung diseases such as bronchopulmonary dysplasia. As alveolar myofibroblasts are involved in the formation of alveoli, the disruption of alveolar myofibroblast proliferation and differentiation can lead to the failure of secondary septum formation and arrested alveoarisation. Therefore, targeting the proliferation and differentiation of alveolar myofibroblast would be an important therapeutic strategy for treating pulmonary diseases.
Led by Professor Bao Shilai from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences, a team of researchers present evidence for protein arginine methyltransferase 7 (PRMT7)’s role in regulating alveolar myofibroblast proliferation and differentiation.
In the study, they examined the function of PRMT7 through tissue-specific knockout mice models and found that PRMT7-deficient mice displayed failure of alveolar septum formation, aberrant elastin deposition, and impaired alveolar myofibroblast proliferation and differentiation.
To further investigate the mechanism behind defects in alveolar myofibroblast proliferation and differentiation in PRMT7-deficient mice, the researchers carried out a series of analyses. From the results, they found one set of cell cycle and cell proliferation regulating genes, including the proliferation-specific transcription factor Foxm1 and its target genes, were noticeably reduced in PRMT7-deficient mice.
Then, the team went on to perform chromatin immunoprecipitation (ChIP) assays to try and determine if Foxm1 is a direct target of PRMT7. The results obtained suggest that Foxm1 is a direct target of PRMT7 and that PRMT7-catalysed monomethylation at histone H4 arginine 3 directly associate with the chromatin of Foxm1 to suppress its transcription, and thereby downregulates the downstream cell cycle-related genes to inhibit alveolar myofibroblast proliferation and differentiation.
In overexpression studies, the overexpression of Foxm1 could rescue both proliferation and differentiation defects in PRMT7-deficient myofibroblasts. Such results suggest that the decreased expression of Foxm1 contributes to aberrant alveolar myofibroblast proliferation and differentiation in PRMT7-deficient mice.
The team’s work has revealed how PRMT7 modulates alveolar myofibroblast proliferation and differentiation during alveologenesis. This could provide a new strategy for therapeutic intervention of pulmonary diseases caused by alveolar myofibroblast dysfunction. [APBN]
Source: He et al. (2021). PRMT7 targets of Foxm1 controls alveolar myofibroblast proliferation and differentiation during alveologenesis. Cell death & disease, 12(9), 1-11.