title: Coactivator-Associated Arginine Methyltransferase-1 Function in Alveolar Epithelial Senescence and Elastase-Induced Emphysema Susceptibility.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible loss of lung function and is one of the most prevalent and severe diseases worldwide. A major feature of COPD is emphysema, which is the progressive loss of alveolar tissue. Coactivator-associated arginine methyltransferase-1 (CARM1) regulates histone methylation and the transcription of genes involved in senescence, proliferation, and differentiation. Complete loss of CARM1 leads to disrupted differentiation and maturation of alveolar epithelial type II (ATII) cells. We thus 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 small interfering (si)RNA-mediated knockdown in ATII-like LA4 cells in vitro. We demonstrate that emphysema progression in vivo is associated with a time-dependent down-regulation of CARM1. Importantly, elastase-treated CARM1 haploinsufficient mice show significantly increased airspace enlargement (52.5 ± 9.6 μm versus 38.8 ± 5.5 μm; P < 0.01) and lung compliance (2.8 ± 0.32 μl/cm H2O versus 2.4 ± 0.4 μl/cm H2O; P < 0.04) compared with controls. The knockdown of CARM1 in LA4 cells led to decreased sirtuin 1 expression (0.034 ± 0.003 versus 0.022 ± 0.001; P < 0.05) but increased expression of p16 (0.27 ± 0.013 versus 0.31 ± 0.010; P < 0.5) and p21 (0.81 ± 0.088 versus 1.28 ± 0.063; P < 0.01) and higher β-galactosidase-positive senescent cells (50.57 ± 7.36% versus 2.21 ± 0.34%; P < 0.001) compared with scrambled siRNA. We further demonstrated that CARM1 haploinsufficiency impairs transdifferentiation and wound healing (32.18 ± 0.9512% versus 8.769 ± 1.967%; P < 0.001) of alveolar epithelial cells. Overall, these results reveal a novel function of CARM1 in regulating emphysema development and premature lung aging via alveolar senescence as well as impaired regeneration, repair, and differentiation of ATII cells.
authors.affiliation: 1 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany.
authors.forename: Rim S J
authors.initials: RS
authors.lastname: Sarker
authors.affiliation: 1 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: John-Schuster
authors.affiliation: 1 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bohla
authors.affiliation: 1 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mutze
authors.affiliation: 1 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Burgstaller
authors.affiliation: 2 Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas; and.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.affiliation: 1 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: 1 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany.|3 University Hospital of the Ludwig-Maximilians-University, München, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: 1 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany.
authors.forename: Ali Ö
authors.initials: AÖ
authors.lastname: Yildirim
mesh_terms: D056809:Alveolar Epithelial Cells / Q000201:enzymology*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D016922:Cellular Senescence; D005260:Female; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase; D011484:Protein-Arginine N-Methyltransferases / Q000502:physiology*; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000201:enzymology*
chemical_list: D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D010196:Pancreatic Elastase
keywords: alveolar type II cells; coactivator-associated arginine methyltransferase 1; elastase-treatment; emphysema; lung regeneration; senescence