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

Andres Ramirez-Martinez; Yichi Zhang; Kenian Chen; Jiwoong Kim; Bercin K. Cenik; John R. McAnally; Chunyu Cai; John M. Shelton; Jian Huang; Ana Brennan; Bret M. Evers; Pradeep P.A. Mammen; Lin Xu; Rhonda Bassel-Duby; Ning Liu; Eric N. Olson

doi:10.1038/s41467-021-20987-x

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

Andres Ramirez-Martinez, Yichi Zhang, Kenian Chen, Jiwoong Kim, Bercin K. Cenik, John R. McAnally, Chunyu Cai, John M. Shelton, Jian Huang, Ana Brennan, Bret M. Evers, Pradeep P.A. Mammen, Lin Xu, Rhonda Bassel-Duby, Ning Liu^*, Eric N. Olson^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

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.

Original language	English (US)
Article number	690
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-20987-x
State	Published - Dec 2021

Funding

We are grateful to J. Cabrera for graphics; R. Deberardinis for helpful discussion; and E. Sanchez-Ortiz, D. Karri, and L. Zacharias for technical assistance and reagents. We thank the Moody Foundation Flow Cytometry Facility for FACS, Children’s Medical Center Research Institute Metabolomics and Sequencing Facilities for metabolomic analysis and next-generation sequencing, respectively, Genomics and Microarray core for RNA-seq, McDermott Next-Generation Sequencing Core for Lamin A/C ChIP library preparation and sequencing, Histo Pathology Core for histological analysis and expertise, UTSW Proteomics core for mass spectrometry, and UTSW Electron Microscopy Core Facility for expert technical assistance. This work was supported by funds from NIH (HL130253, AR071980 and AR-067294), the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center (U54 HD 087351), the Robert A. Welch Foundation (grant 1-0025 to E.N.O.), and the Canada Institute of Health Research Doctoral Foreign Study Award (DFS164267 to Y.Z.).

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Ramirez-Martinez, A., Zhang, Y., Chen, K., Kim, J., Cenik, B. K., McAnally, J. R., Cai, C., Shelton, J. M., Huang, J., Brennan, A., Evers, B. M., Mammen, P. P. A., Xu, L., Bassel-Duby, R., Liu, N., & Olson, E. N. (2021). The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization. Nature communications, 12(1), Article 690. https://doi.org/10.1038/s41467-021-20987-x

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title = "The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization",

abstract = "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.",

author = "Andres Ramirez-Martinez and Yichi Zhang and Kenian Chen and Jiwoong Kim and Cenik, {Bercin K.} and McAnally, {John R.} and Chunyu Cai and Shelton, {John M.} and Jian Huang and Ana Brennan and Evers, {Bret M.} and Mammen, {Pradeep P.A.} and Lin Xu and Rhonda Bassel-Duby and Ning Liu and Olson, {Eric N.}",

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year = "2021",

month = dec,

doi = "10.1038/s41467-021-20987-x",

language = "English (US)",

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Ramirez-Martinez, A, Zhang, Y, Chen, K, Kim, J, Cenik, BK, McAnally, JR, Cai, C, Shelton, JM, Huang, J, Brennan, A, Evers, BM, Mammen, PPA, Xu, L, Bassel-Duby, R, Liu, N & Olson, EN 2021, 'The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization', Nature communications, vol. 12, no. 1, 690. https://doi.org/10.1038/s41467-021-20987-x

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AU - Ramirez-Martinez, Andres

AU - Zhang, Yichi

AU - Chen, Kenian

AU - Kim, Jiwoong

AU - Cenik, Bercin K.

AU - McAnally, John R.

AU - Cai, Chunyu

AU - Shelton, John M.

AU - Huang, Jian

AU - Brennan, Ana

AU - Evers, Bret M.

AU - Mammen, Pradeep P.A.

AU - Xu, Lin

AU - Bassel-Duby, Rhonda

AU - Liu, Ning

AU - Olson, Eric N.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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

Abstract

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