PRMT1 Deficiency in Mouse Juvenile Heart Induces Dilated Cardiomyopathy and Reveals Cryptic Alternative Splicing Products
Kazuya Murata,
Weizhe Lu,
Misuzu Hashimoto,
Natsumi Ono,
Masafumi Muratani,
Kana Nishikata,
Jun-Dal Kim,
Shizufumi Ebihara,
Junji Ishida,
Akiyoshi Fukamizu
Affiliations
Kazuya Murata
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Weizhe Lu
Ph.D. Program in Human Biology, School of Integrative Global Majors (SIGMA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Misuzu Hashimoto
Ph.D. Program in Human Biology, School of Integrative Global Majors (SIGMA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu 501-1193, Japan
Natsumi Ono
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Masafumi Muratani
Department of Genome Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Genome Biology Core, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
Kana Nishikata
Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan
Jun-Dal Kim
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Shizufumi Ebihara
Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan
Junji Ishida
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Akiyoshi Fukamizu
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Corresponding author
Summary: Protein arginine methyltransferase 1 (PRMT1) catalyzes the asymmetric dimethylation of arginine residues in proteins and methylation of various RNA-binding proteins and is associated with alternative splicing in vitro. Although PRMT1 has essential in vivo roles in embryonic development, CNS development, and skeletal muscle regeneration, the functional importance of PRMT1 in the heart remains to be elucidated. Here, we report that juvenile cardiomyocyte-specific PRMT1-deficient mice develop severe dilated cardiomyopathy and exhibit aberrant cardiac alternative splicing. Furthermore, we identified previously undefined cardiac alternative splicing isoforms of four genes (Asb2, Fbxo40, Nrap, and Eif4a2) in PRMT1-cKO mice and revealed that eIF4A2 protein isoforms translated from alternatively spliced mRNA were differentially ubiquitinated and degraded by the ubiquitin-proteasome system. These findings highlight the essential roles of PRMT1 in cardiac homeostasis and alternative splicing regulation. : Genetics; Molecular Biology; Cell Biology; Developmental Biology Subject Areas: Genetics, Molecular Biology, Cell Biology, Developmental Biology