Role of CARM1 in regulation of alveolar epithelial senescence and emphysema susceptibility

Chronic obstructive pulmonary disease (COPD) is characterized by an
irreversible loss of lung function and is one of the most prevalent
and severe diseases world-wide. A major feature of COPD is
emphysema- a long-term, progressive condition. The hallmark of
emphysema includes the destruction of alveolar structures leading
to enlarged air spaces and reduced surface area. Experimental
evidence suggests that emphysema development is driven by
accelerated senescence of lung cells but the underlying mechanism
of senescence is yet to be fully elucidated. Protein arginine
methyltransferases (PRMTs) are important for cellular processes,
such as the regulation of senescence, cell proliferation,
differentiation and apoptosis. The PRMT family includes 11 members
classified as type I, II or III enzymes depending on their
methylation pattern (asymmetric dimethylation, symmetric
dimethylation or monomethylation, respectively). One member of this
family is PRMT4, a type I enzyme, which is also called coactivator
associated arginine methyltransferase 1 (CARM1). It was originally
identified as a coactivator for steroid hormone receptors. CARM1 is
known to methylate histone H3 and various non-histone proteins that
play essential roles in transcriptional regulation, RNA splicing,
and metabolism. Most importantly, complete loss of CARM1 leads to
disrupted differentiation and maturation of alveolar epithelial
type-II cells (ATII). Furthermore, CARM1 also plays a role in
regulating cellular senescence via CARM1-dependent methylation.
Based on these reports, we hypothesized that CARM1 regulates the
development and progression of emphysema. To address this, we
investigated the contribution of CARM1 to alveolar rarefication
using the mouse model of elastase-induced emphysema in vivo and
siRNA-mediated knockdown in ATII-like LA4 cells in vitro. We
monitored emphysema progression for 161 days in mice treated with a
single oropharyngeal application of elastase. The progression was
manifested by the decline in lung function parameters. The mean
chord length (Lm) confirmed a time dependent airspace enlargement
and was directly correlated with a significant increase in dynamic
lung compliance. We also observed that at later time points (day 56
and 161), emphysema progression was inflammation-independent. We
demonstrated that emphysema advancement was associated with a
time-dependent downregulation of CARM1, specifically in alveolar
epithelial cells. Furthermore, the global CARM1 activity was also
reduced as reflected by an elevated level of CARM1 phosphorylation
in the lung. Most importantly, elastase-treated CARM1
haploinsufficient mice showed significantly increased airspace
enlargement (52.5±9.6 µm vs. 38.8±5.5 µm, p