Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential

X-chromosome dosage compensation in female mammals is achieved through X-chromosome inactivation (XCI), where one X chromosome is epigenetically silenced to ensure dosage parity with male cells. During germline development, this silenced X chromosome reactivates before the onset of meiosis, however...

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Detalles Bibliográficos
Autor: Mattimoe, Tom
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/692844
Acceso en línea:http://hdl.handle.net/10803/692844
Access Level:acceso embargado
Palabra clave:Stem cells
Germline
X chromosome
Meiosis
Methylation
Células madre
Línea germinal
Cromosoma X
Metilación
576
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spelling Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potentialMattimoe, TomStem cellsGermlineX chromosomeMeiosisMethylationCélulas madreLínea germinalCromosoma XMetilación576X-chromosome dosage compensation in female mammals is achieved through X-chromosome inactivation (XCI), where one X chromosome is epigenetically silenced to ensure dosage parity with male cells. During germline development, this silenced X chromosome reactivates before the onset of meiosis, however the exact requirements for this remain to be fully characterised. In this thesis, I investigate the significance of X-chromosome dosage regulation in the female germline using an in vitro approach. We generated a dual X-chromosome reporter mouse embryonic stem cell line with a knockout of Xist, the long non-coding RNA responsible for mediating XCI. Our results demonstrate that most cells fail to maintain two active X chromosomes upon exiting pluripotency, leading to either X-chromosome loss or cell death. However, a subset of primordial germ cell-like cells (PGCLCs) that survive this bottleneck with two active X chromosomes progress efficiently to meiosis prophase I. Additionally, we find that X-chromosome dosage significantly influences the transcriptomic and epigenetic landscapes of PGCLCs. These findings offer new insights into the epigenetic prerequisites for proper meiotic entry in female germ cells and underscore the critical role of X-chromosome dosage in germline development.La compensación de la dosis del cromosoma X en mamíferos femeninos se logra a través de la inactivación del cromosoma X (ICX), un proceso en el que uno de los cromosomas X es silenciado epigenéticamente para garantizar la paridad de dosis con las células masculinas. Durante el desarrollo de la línea germinal, este cromosoma X silenciado se reactiva antes del inicio de la meiosis, aunque los requisitos exactos para este proceso aún no se han caracterizado completamente. En esta tesis, investigamos la importancia de la regulación de la dosis del cromosoma X en el contexto de la línea germinal femenina utilizando un enfoque in vitro. Generamos una línea celular de embriones de ratón con un doble reportero de cromosoma X y una deleción de Xist, el ARN largo no codificante responsable de mediar la ICX. Nuestros resultados demuestran que la mayoría de las células no pueden mantener dos cromosomas X activos al salir de la pluripotencia, lo que lleva a la pérdida del cromosoma X o a la muerte celular. Sin embargo, un subconjunto de células similares a las células germinales primordiales (PGCLCs) que sobreviven a este cuello de botella con dos cromosomas X activos progresa eficientemente a la profase I de la meiosis. Además, encontramos que la dosis del cromosoma X influye significativamente en las características transcriptómicas y epigenéticas de las PGCLCs. Estos hallazgos ofrecen nuevas perspectivas sobre los requisitos epigenéticos para la correcta entrada en la meiosis en las células germinales femeninas y demuestran el papel crucial de la dosis del cromosoma X en el desarrollo de la línea germinal.Programa de Doctorat en BiomedicinaUniversitat Pompeu FabraPayer, BernhardUniversitat Pompeu Fabra. Departament de Medicina i Ciències de la Vida202420242026info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion108 p.application/pdfhttp://hdl.handle.net/10803/692844TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc/4.0/http://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/embargoedAccessoai:www.tdx.cat:10803/6928442026-06-14T12:46:07Z
dc.title.none.fl_str_mv Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential
title Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential
spellingShingle Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential
Mattimoe, Tom
Stem cells
Germline
X chromosome
Meiosis
Methylation
Células madre
Línea germinal
Cromosoma X
Metilación
576
title_short Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential
title_full Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential
title_fullStr Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential
title_full_unstemmed Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential
title_sort Interrogating the importance of x-chromosome inactivation and reactivation for meiotic potential
dc.creator.none.fl_str_mv Mattimoe, Tom
author Mattimoe, Tom
author_facet Mattimoe, Tom
author_role author
dc.contributor.none.fl_str_mv Payer, Bernhard
Universitat Pompeu Fabra. Departament de Medicina i Ciències de la Vida
dc.subject.none.fl_str_mv Stem cells
Germline
X chromosome
Meiosis
Methylation
Células madre
Línea germinal
Cromosoma X
Metilación
576
topic Stem cells
Germline
X chromosome
Meiosis
Methylation
Células madre
Línea germinal
Cromosoma X
Metilación
576
description X-chromosome dosage compensation in female mammals is achieved through X-chromosome inactivation (XCI), where one X chromosome is epigenetically silenced to ensure dosage parity with male cells. During germline development, this silenced X chromosome reactivates before the onset of meiosis, however the exact requirements for this remain to be fully characterised. In this thesis, I investigate the significance of X-chromosome dosage regulation in the female germline using an in vitro approach. We generated a dual X-chromosome reporter mouse embryonic stem cell line with a knockout of Xist, the long non-coding RNA responsible for mediating XCI. Our results demonstrate that most cells fail to maintain two active X chromosomes upon exiting pluripotency, leading to either X-chromosome loss or cell death. However, a subset of primordial germ cell-like cells (PGCLCs) that survive this bottleneck with two active X chromosomes progress efficiently to meiosis prophase I. Additionally, we find that X-chromosome dosage significantly influences the transcriptomic and epigenetic landscapes of PGCLCs. These findings offer new insights into the epigenetic prerequisites for proper meiotic entry in female germ cells and underscore the critical role of X-chromosome dosage in germline development.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2026
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 http://hdl.handle.net/10803/692844
url http://hdl.handle.net/10803/692844
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/embargoedAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv 108 p.
application/pdf
dc.publisher.none.fl_str_mv Universitat Pompeu Fabra
publisher.none.fl_str_mv Universitat Pompeu Fabra
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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