The nuclear pore protein Nup153 associates with chromatin and regulates cardiac gene expression in dystrophic mdx hearts

Simona Nanni, Agnese Re, Cristian Ripoli, Aoife Gowran, Patrizia Nigro, Domenico D'Amario, Antonio Amodeo, Filippo Crea, Claudio Grassi, Alfredo Pontecorvi, Antonella Farsetti, Claudia Colussi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Aims Beyond the control of nuclear-cytoplasmic trafficking nucleoporins regulate gene expression and are involved in cardiac diseases. Notably, a number of cardiovascular disorders have been linked to alterations in epigenetic mechanisms. Here we aimed to determine the contribution of Nup153 to the epigenetic alterations occurring in cardiomyopathy of dystrophin-deficient mdx mice (C57BL/10ScSn-Dmdmdx/J). Methods and results Nup153 was lysine-acetylated and its expression was significantly increased at protein level in mdx hearts compared with controls. Accordingly, lysine acetyl transferase (KAT) activity associated with Nup153 was higher in mdx hearts paralleling increased binding with the lysine acetylases P300/CBP-associated factor (PCAF) and p300. Interestingly, Nup153 silencing in mdx organotypic heart tissue slices caused a reduction in PCAF- and p300-specific activities. Remarkably, the level of nitric oxide (NO), which is reduced in mdx mice, was important for KAT-dependent regulation of Nup153. In fact, treatment of mdx heart tissue with an NO donor or the KAT inhibitor anacardic acid normalized Nup153 protein expression. Nup153 was recruited to chromatin and regulated the transcription of genes involved in cardiac remodelling, including the actin-binding protein nexilin. Accordingly, nexilin protein expression was abrogated by Nup153 silencing in mdx organotypic cultures. Electrophysiological and molecular experiments revealed that Nup153 overexpression in normal cardiomyocytes increases Cav1.2 calcium channel expression and function. Alterations in Nup153 protein expression and intracellular localization were also found in dystrophic cardiomyocytes derived from patient-specific induced pluripotent stem cells. Importantly, Nup153 up-regulation and increased acetylation were also found in the heart of Duchenne muscular dystrophy patients. Conclusions Our data indicate that Nup153 is an epigenetic regulator which, upon altered NO signalling, mediates the activation of genes potentially associated with early dystrophic cardiac remodelling.

Original languageEnglish
Pages (from-to)555-567
Number of pages13
JournalCardiovascular Research
Volume112
Issue number2
DOIs
Publication statusPublished - Nov 1 2016

Fingerprint

Nuclear Pore
Porins
Nuclear Proteins
Chromatin
Gene Expression
Epigenomics
Inbred mdx Mouse
Lysine
Cardiac Myocytes
Nitric Oxide
Proteins
Nuclear Pore Complex Proteins
Acetylesterase
Microfilament Proteins
Induced Pluripotent Stem Cells
Dystrophin
Duchenne Muscular Dystrophy
Nitric Oxide Donors
Acetylation
Transferases

Keywords

  • Acetylation
  • Chromatin immunoprecipitation
  • Muscular dystrophy
  • Nitric oxide
  • Nucleoporin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

The nuclear pore protein Nup153 associates with chromatin and regulates cardiac gene expression in dystrophic mdx hearts. / Nanni, Simona; Re, Agnese; Ripoli, Cristian; Gowran, Aoife; Nigro, Patrizia; D'Amario, Domenico; Amodeo, Antonio; Crea, Filippo; Grassi, Claudio; Pontecorvi, Alfredo; Farsetti, Antonella; Colussi, Claudia.

In: Cardiovascular Research, Vol. 112, No. 2, 01.11.2016, p. 555-567.

Research output: Contribution to journalArticle

Nanni, S, Re, A, Ripoli, C, Gowran, A, Nigro, P, D'Amario, D, Amodeo, A, Crea, F, Grassi, C, Pontecorvi, A, Farsetti, A & Colussi, C 2016, 'The nuclear pore protein Nup153 associates with chromatin and regulates cardiac gene expression in dystrophic mdx hearts', Cardiovascular Research, vol. 112, no. 2, pp. 555-567. https://doi.org/10.1093/cvr/cvw204
Nanni, Simona ; Re, Agnese ; Ripoli, Cristian ; Gowran, Aoife ; Nigro, Patrizia ; D'Amario, Domenico ; Amodeo, Antonio ; Crea, Filippo ; Grassi, Claudio ; Pontecorvi, Alfredo ; Farsetti, Antonella ; Colussi, Claudia. / The nuclear pore protein Nup153 associates with chromatin and regulates cardiac gene expression in dystrophic mdx hearts. In: Cardiovascular Research. 2016 ; Vol. 112, No. 2. pp. 555-567.
@article{bbbc2faba8454f12b13e8944ccc40dfa,
title = "The nuclear pore protein Nup153 associates with chromatin and regulates cardiac gene expression in dystrophic mdx hearts",
abstract = "Aims Beyond the control of nuclear-cytoplasmic trafficking nucleoporins regulate gene expression and are involved in cardiac diseases. Notably, a number of cardiovascular disorders have been linked to alterations in epigenetic mechanisms. Here we aimed to determine the contribution of Nup153 to the epigenetic alterations occurring in cardiomyopathy of dystrophin-deficient mdx mice (C57BL/10ScSn-Dmdmdx/J). Methods and results Nup153 was lysine-acetylated and its expression was significantly increased at protein level in mdx hearts compared with controls. Accordingly, lysine acetyl transferase (KAT) activity associated with Nup153 was higher in mdx hearts paralleling increased binding with the lysine acetylases P300/CBP-associated factor (PCAF) and p300. Interestingly, Nup153 silencing in mdx organotypic heart tissue slices caused a reduction in PCAF- and p300-specific activities. Remarkably, the level of nitric oxide (NO), which is reduced in mdx mice, was important for KAT-dependent regulation of Nup153. In fact, treatment of mdx heart tissue with an NO donor or the KAT inhibitor anacardic acid normalized Nup153 protein expression. Nup153 was recruited to chromatin and regulated the transcription of genes involved in cardiac remodelling, including the actin-binding protein nexilin. Accordingly, nexilin protein expression was abrogated by Nup153 silencing in mdx organotypic cultures. Electrophysiological and molecular experiments revealed that Nup153 overexpression in normal cardiomyocytes increases Cav1.2 calcium channel expression and function. Alterations in Nup153 protein expression and intracellular localization were also found in dystrophic cardiomyocytes derived from patient-specific induced pluripotent stem cells. Importantly, Nup153 up-regulation and increased acetylation were also found in the heart of Duchenne muscular dystrophy patients. Conclusions Our data indicate that Nup153 is an epigenetic regulator which, upon altered NO signalling, mediates the activation of genes potentially associated with early dystrophic cardiac remodelling.",
keywords = "Acetylation, Chromatin immunoprecipitation, Muscular dystrophy, Nitric oxide, Nucleoporin",
author = "Simona Nanni and Agnese Re and Cristian Ripoli and Aoife Gowran and Patrizia Nigro and Domenico D'Amario and Antonio Amodeo and Filippo Crea and Claudio Grassi and Alfredo Pontecorvi and Antonella Farsetti and Claudia Colussi",
year = "2016",
month = "11",
day = "1",
doi = "10.1093/cvr/cvw204",
language = "English",
volume = "112",
pages = "555--567",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - The nuclear pore protein Nup153 associates with chromatin and regulates cardiac gene expression in dystrophic mdx hearts

AU - Nanni, Simona

AU - Re, Agnese

AU - Ripoli, Cristian

AU - Gowran, Aoife

AU - Nigro, Patrizia

AU - D'Amario, Domenico

AU - Amodeo, Antonio

AU - Crea, Filippo

AU - Grassi, Claudio

AU - Pontecorvi, Alfredo

AU - Farsetti, Antonella

AU - Colussi, Claudia

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Aims Beyond the control of nuclear-cytoplasmic trafficking nucleoporins regulate gene expression and are involved in cardiac diseases. Notably, a number of cardiovascular disorders have been linked to alterations in epigenetic mechanisms. Here we aimed to determine the contribution of Nup153 to the epigenetic alterations occurring in cardiomyopathy of dystrophin-deficient mdx mice (C57BL/10ScSn-Dmdmdx/J). Methods and results Nup153 was lysine-acetylated and its expression was significantly increased at protein level in mdx hearts compared with controls. Accordingly, lysine acetyl transferase (KAT) activity associated with Nup153 was higher in mdx hearts paralleling increased binding with the lysine acetylases P300/CBP-associated factor (PCAF) and p300. Interestingly, Nup153 silencing in mdx organotypic heart tissue slices caused a reduction in PCAF- and p300-specific activities. Remarkably, the level of nitric oxide (NO), which is reduced in mdx mice, was important for KAT-dependent regulation of Nup153. In fact, treatment of mdx heart tissue with an NO donor or the KAT inhibitor anacardic acid normalized Nup153 protein expression. Nup153 was recruited to chromatin and regulated the transcription of genes involved in cardiac remodelling, including the actin-binding protein nexilin. Accordingly, nexilin protein expression was abrogated by Nup153 silencing in mdx organotypic cultures. Electrophysiological and molecular experiments revealed that Nup153 overexpression in normal cardiomyocytes increases Cav1.2 calcium channel expression and function. Alterations in Nup153 protein expression and intracellular localization were also found in dystrophic cardiomyocytes derived from patient-specific induced pluripotent stem cells. Importantly, Nup153 up-regulation and increased acetylation were also found in the heart of Duchenne muscular dystrophy patients. Conclusions Our data indicate that Nup153 is an epigenetic regulator which, upon altered NO signalling, mediates the activation of genes potentially associated with early dystrophic cardiac remodelling.

AB - Aims Beyond the control of nuclear-cytoplasmic trafficking nucleoporins regulate gene expression and are involved in cardiac diseases. Notably, a number of cardiovascular disorders have been linked to alterations in epigenetic mechanisms. Here we aimed to determine the contribution of Nup153 to the epigenetic alterations occurring in cardiomyopathy of dystrophin-deficient mdx mice (C57BL/10ScSn-Dmdmdx/J). Methods and results Nup153 was lysine-acetylated and its expression was significantly increased at protein level in mdx hearts compared with controls. Accordingly, lysine acetyl transferase (KAT) activity associated with Nup153 was higher in mdx hearts paralleling increased binding with the lysine acetylases P300/CBP-associated factor (PCAF) and p300. Interestingly, Nup153 silencing in mdx organotypic heart tissue slices caused a reduction in PCAF- and p300-specific activities. Remarkably, the level of nitric oxide (NO), which is reduced in mdx mice, was important for KAT-dependent regulation of Nup153. In fact, treatment of mdx heart tissue with an NO donor or the KAT inhibitor anacardic acid normalized Nup153 protein expression. Nup153 was recruited to chromatin and regulated the transcription of genes involved in cardiac remodelling, including the actin-binding protein nexilin. Accordingly, nexilin protein expression was abrogated by Nup153 silencing in mdx organotypic cultures. Electrophysiological and molecular experiments revealed that Nup153 overexpression in normal cardiomyocytes increases Cav1.2 calcium channel expression and function. Alterations in Nup153 protein expression and intracellular localization were also found in dystrophic cardiomyocytes derived from patient-specific induced pluripotent stem cells. Importantly, Nup153 up-regulation and increased acetylation were also found in the heart of Duchenne muscular dystrophy patients. Conclusions Our data indicate that Nup153 is an epigenetic regulator which, upon altered NO signalling, mediates the activation of genes potentially associated with early dystrophic cardiac remodelling.

KW - Acetylation

KW - Chromatin immunoprecipitation

KW - Muscular dystrophy

KW - Nitric oxide

KW - Nucleoporin

UR - http://www.scopus.com/inward/record.url?scp=84994462014&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994462014&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvw204

DO - 10.1093/cvr/cvw204

M3 - Article

VL - 112

SP - 555

EP - 567

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 2

ER -