The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization

• Published in: Nature communications 2021-01, Vol.12 (1), p.690-690, Article 690
• Main Authors: Ramirez-Martinez, Andres, Zhang, Yichi, Chen, Kenian, Kim, Jiwoong, Cenik, Bercin K., McAnally, John R., Cai, Chunyu, Shelton, John M., Huang, Jian, Brennan, Ana, Evers, Bret M., Mammen, Pradeep P. A., Xu, Lin, Bassel-Duby, Rhonda, Liu, Ning, Olson, Eric N.
• Format: Article
• Language: English
• Subjects: 14/28; 38; 45/15; 631/337/386; 64/60; 692/698/1671; 692/699/375/374; 82/80; Abnormalities; Animals; Cell Line; Chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation Sequencing; Disease Models, Animal; Down-Regulation; Dystrophy; Etiology; Female; Gene expression; Genomes; Humanities and Social Sciences; Humans; Integrity; Lamin Type A - genetics; Lamins; Lethality; Male; Membrane proteins; Membrane Proteins - deficiency; Membrane Proteins - genetics; Metabolism; Mice; Mice, Knockout; multidisciplinary; Muscle, Skeletal - cytology; Muscle, Skeletal - pathology; Muscles; Muscular dystrophy; Muscular Dystrophy, Emery-Dreifuss - genetics; Muscular Dystrophy, Emery-Dreifuss - pathology; Mutation; Myopathy; Nuclear Envelope - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear structure; Pathogenesis; Phosphatidate Phosphatase - genetics; Phosphatidate Phosphatase - metabolism; Proteins; Retrospective Studies; RNA-Seq; Science; Science (multidisciplinary); Tethers; Viral envelope proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-20987-x

Lamins and transmembrane proteins within the nuclear envelope regulate nuclear structure and chromatin organization. Nuclear envelope transmembrane protein 39 (Net39) is a muscle nuclear envelope protein whose functions in vivo have not been explored. We show that mice lacking Net39 succumb to severe myopathy and juvenile lethality, with concomitant disruption in nuclear integrity, chromatin accessibility, gene expression, and metabolism. These abnormalities resemble those of Emery–Dreifuss muscular dystrophy (EDMD), caused by mutations in A-type lamins ( LMNA ) and other genes, like Emerin ( EMD ). We observe that Net39 is downregulated in EDMD patients, implicating Net39 in the pathogenesis of this disorder. Our findings highlight the role of Net39 at the nuclear envelope in maintaining muscle chromatin organization, gene expression and function, and its potential contribution to the molecular etiology of EDMD. The nuclear envelope tethers chromatin to the nuclear periphery to control genome architecture. Here, the authors show that Net39 preserves the integrity and gene expression of muscle nuclei in mice, and it may contribute to the pathogenesis of Emery–Dreifuss muscular dystrophy.