Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression

[eng] The application of mechanical force to the nucleus has been recently shown to regulate important functions, including nucleocytoplasmic transport (NCT), chromatin organization, and gene expression. However, how substrate rigidity and the subsequent transmission of force to the nucleus impacts...

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Detalhes bibliográficos
Autor: Molina Jordán, Marc
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/207041
Acesso em linha:https://hdl.handle.net/2445/207041
http://hdl.handle.net/10803/689955
Access Level:acceso abierto
Palavra-chave:Genòmica
Transcripció genètica
Teoria del transport
Nuclis cel·lulars
Regulació cel·lular
Genomics
Genetic transcription
Transport theory
Cell nuclei
Cellular control mechanisms
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spelling Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expressionMolina Jordán, MarcGenòmicaTranscripció genèticaTeoria del transportNuclis cel·lularsRegulació cel·lularGenomicsGenetic transcriptionTransport theoryCell nucleiCellular control mechanisms[eng] The application of mechanical force to the nucleus has been recently shown to regulate important functions, including nucleocytoplasmic transport (NCT), chromatin organization, and gene expression. However, how substrate rigidity and the subsequent transmission of force to the nucleus impacts nuclear function and dynamics is still poorly understood. Here we focus on two aspects: the effect of nuclear force in NPCs and in chromatin organization and gene expression. We show how knockdown (KD) of two key NPC structural components, namely NUP155 and NUP153, decrease the accumulation of the transcriptional regulator (TR) YAP/TAZ to the nucleus as well as disrupt NCT in mammalian cells. With the aim to analyze structural changes in nuclear pores we perform super-resolution microscopy (SRM) and establish a method to image cells on substrates of different stiffness. In this set up and using U-2 osteosarcoma (U-2 OS) cells we do not observe rigidity or KD-dependent changes in NPC size. However, we suspect that these results arise from cell type or NUP-specific conditions and propose new candidates to test our new hypothesis. In addition, we use substrate stiffness to characterize via Hi-C and RNA-sequencing the force-dependent changes in chromatin state and transcription. Our results show that biomechanical manipulation using mutants to impair mechanosensitive NCT as well as substrate stiffness affects the functional organization of topologically associated domains (TADs) as well as the expression of genes linked to the cytoskeleton, focal adhesions, and the NPC.Universitat de BarcelonaRoca-Cusachs Soulere, PereAndreu Arzuaga, IonUniversitat de Barcelona. Facultat de Biologia2023info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/207041http://hdl.handle.net/10803/689955Tesis Doctorals - Facultat - Biologiareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléscc by-nc-nd (c) Molina Jordán, Marc, 2024http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2070412026-05-27T06:46:51Z
dc.title.none.fl_str_mv Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression
title Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression
spellingShingle Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression
Molina Jordán, Marc
Genòmica
Transcripció genètica
Teoria del transport
Nuclis cel·lulars
Regulació cel·lular
Genomics
Genetic transcription
Transport theory
Cell nuclei
Cellular control mechanisms
title_short Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression
title_full Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression
title_fullStr Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression
title_full_unstemmed Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression
title_sort Study of the role of substrate stiffness and force transmission to the nucleus in nucleocytoplasmic transport, nuclear pore conformation, genome organization and gene expression
dc.creator.none.fl_str_mv Molina Jordán, Marc
author Molina Jordán, Marc
author_facet Molina Jordán, Marc
author_role author
dc.contributor.none.fl_str_mv Roca-Cusachs Soulere, Pere
Andreu Arzuaga, Ion
Universitat de Barcelona. Facultat de Biologia
dc.subject.none.fl_str_mv Genòmica
Transcripció genètica
Teoria del transport
Nuclis cel·lulars
Regulació cel·lular
Genomics
Genetic transcription
Transport theory
Cell nuclei
Cellular control mechanisms
topic Genòmica
Transcripció genètica
Teoria del transport
Nuclis cel·lulars
Regulació cel·lular
Genomics
Genetic transcription
Transport theory
Cell nuclei
Cellular control mechanisms
description [eng] The application of mechanical force to the nucleus has been recently shown to regulate important functions, including nucleocytoplasmic transport (NCT), chromatin organization, and gene expression. However, how substrate rigidity and the subsequent transmission of force to the nucleus impacts nuclear function and dynamics is still poorly understood. Here we focus on two aspects: the effect of nuclear force in NPCs and in chromatin organization and gene expression. We show how knockdown (KD) of two key NPC structural components, namely NUP155 and NUP153, decrease the accumulation of the transcriptional regulator (TR) YAP/TAZ to the nucleus as well as disrupt NCT in mammalian cells. With the aim to analyze structural changes in nuclear pores we perform super-resolution microscopy (SRM) and establish a method to image cells on substrates of different stiffness. In this set up and using U-2 osteosarcoma (U-2 OS) cells we do not observe rigidity or KD-dependent changes in NPC size. However, we suspect that these results arise from cell type or NUP-specific conditions and propose new candidates to test our new hypothesis. In addition, we use substrate stiffness to characterize via Hi-C and RNA-sequencing the force-dependent changes in chromatin state and transcription. Our results show that biomechanical manipulation using mutants to impair mechanosensitive NCT as well as substrate stiffness affects the functional organization of topologically associated domains (TADs) as well as the expression of genes linked to the cytoskeleton, focal adhesions, and the NPC.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/207041
http://hdl.handle.net/10803/689955
url https://hdl.handle.net/2445/207041
http://hdl.handle.net/10803/689955
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv cc by-nc-nd (c) Molina Jordán, Marc, 2024
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Molina Jordán, Marc, 2024
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Biologia
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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