The Role of histone variant macroH2A1 in muscle physiology and pathophysiology

MacroH2A1.1 is one of the least understood histone variants and structural components of chromatin. Generated by alternative splicing, macroH2A1.1 differs from the other macroH2A1 isoform in its capacity to bind NAD+-derived metabolites in vitro. This observation intrigued us to speculate that macro...

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Detalhes bibliográficos
Autor: Posavec, Melanija
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2014
País:España
Recursos:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/316789
Acesso em linha:http://hdl.handle.net/10803/316789
Access Level:acceso abierto
Palavra-chave:Histones
Nucleosome
Chromatin
macroH2A1.1
macroH2A1.2
Splicing isoforms
Exon
NAD+ metabolismo
Epigenética
Nucleosoma
Variante de histona
Splicing alternativo
Músculo esquelético
Fibras oxidativas
Fibras glucolíticas
Atrofia muscular
616.7
id ES_40ef47e1d4b80f5e321fdd391d708cb9
oai_identifier_str oai:www.tdx.cat:10803/316789
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
title The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
spellingShingle The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
Posavec, Melanija
Histones
Nucleosome
Chromatin
macroH2A1.1
macroH2A1.2
Splicing isoforms
Exon
NAD+ metabolismo
Epigenética
Nucleosoma
Variante de histona
Splicing alternativo
Músculo esquelético
Fibras oxidativas
Fibras glucolíticas
Atrofia muscular
616.7
title_short The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
title_full The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
title_fullStr The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
title_full_unstemmed The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
title_sort The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
dc.creator.none.fl_str_mv Posavec, Melanija
author Posavec, Melanija
author_facet Posavec, Melanija
author_role author
dc.contributor.none.fl_str_mv Buschbeck, Marcus
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.subject.none.fl_str_mv Histones
Nucleosome
Chromatin
macroH2A1.1
macroH2A1.2
Splicing isoforms
Exon
NAD+ metabolismo
Epigenética
Nucleosoma
Variante de histona
Splicing alternativo
Músculo esquelético
Fibras oxidativas
Fibras glucolíticas
Atrofia muscular
616.7
topic Histones
Nucleosome
Chromatin
macroH2A1.1
macroH2A1.2
Splicing isoforms
Exon
NAD+ metabolismo
Epigenética
Nucleosoma
Variante de histona
Splicing alternativo
Músculo esquelético
Fibras oxidativas
Fibras glucolíticas
Atrofia muscular
616.7
description MacroH2A1.1 is one of the least understood histone variants and structural components of chromatin. Generated by alternative splicing, macroH2A1.1 differs from the other macroH2A1 isoform in its capacity to bind NAD+-derived metabolites in vitro. This observation intrigued us to speculate that macroH2A1.1 could link metabolic and epigenetic regulation. To test the importance of this observation, we turned to skeletal muscle as this tissue is expressing the highest levels of the metabolite-binding isoforms. We demonstrate a switch in macroH2A1 splicing from the metabolite non-binding isoform to macroH2A1.1 during normal myogenic differentiation. We demonstrate that macroH2A1.1 and partly the integrity of its metabolite-binding pocket are important for proper myoblast fusion and myotube maturation. We describe the altered bioenergetic and metabolic phenotype in macroH2A1.1-depleted cells and correlate it to transcriptional alterations of genes. These include genes encoding myosin heavy chain proteins, that are markers of muscle fibers differing in their metabolic function. Correspondingly, we demonstrate a shift in the fiber type composition of skeletal muscles from adult macroH2A1-deficient mice. Therefore, we suggest that macroH2A1.1 is one of the epigenetic factors that define the metabolic responsiveness of muscle relevant for whole body health and metabolic homeostasis. We further venture the speculation that the alterations in skeletal muscles of macroH2A1- deficient mice could contribute to their pre-diabetic phenotype.
publishDate 2014
dc.date.none.fl_str_mv 2014
2015
2015
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/10803/316789
url http://hdl.handle.net/10803/316789
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 191 p.
application/pdf
application/pdf
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
_version_ 1869406811952513024
spelling The Role of histone variant macroH2A1 in muscle physiology and pathophysiologyPosavec, MelanijaHistonesNucleosomeChromatinmacroH2A1.1macroH2A1.2Splicing isoformsExonNAD+ metabolismoEpigenéticaNucleosomaVariante de histonaSplicing alternativoMúsculo esqueléticoFibras oxidativasFibras glucolíticasAtrofia muscular616.7MacroH2A1.1 is one of the least understood histone variants and structural components of chromatin. Generated by alternative splicing, macroH2A1.1 differs from the other macroH2A1 isoform in its capacity to bind NAD+-derived metabolites in vitro. This observation intrigued us to speculate that macroH2A1.1 could link metabolic and epigenetic regulation. To test the importance of this observation, we turned to skeletal muscle as this tissue is expressing the highest levels of the metabolite-binding isoforms. We demonstrate a switch in macroH2A1 splicing from the metabolite non-binding isoform to macroH2A1.1 during normal myogenic differentiation. We demonstrate that macroH2A1.1 and partly the integrity of its metabolite-binding pocket are important for proper myoblast fusion and myotube maturation. We describe the altered bioenergetic and metabolic phenotype in macroH2A1.1-depleted cells and correlate it to transcriptional alterations of genes. These include genes encoding myosin heavy chain proteins, that are markers of muscle fibers differing in their metabolic function. Correspondingly, we demonstrate a shift in the fiber type composition of skeletal muscles from adult macroH2A1-deficient mice. Therefore, we suggest that macroH2A1.1 is one of the epigenetic factors that define the metabolic responsiveness of muscle relevant for whole body health and metabolic homeostasis. We further venture the speculation that the alterations in skeletal muscles of macroH2A1- deficient mice could contribute to their pre-diabetic phenotype.MacroH2A1.1 es una de las variantes de histonas y componentes estructurales de la cromatina menos comprendidos. MacroH2A1.1 es generado por splicing alternativo y difiere de la otra isoforma de macroH2A1 en su capacidad para unirse a metabolitos derivados de NAD+ in vitro. Esta observación nos intrigó a especular que macroH2A1.1 podría vincular metabolismo y regulación epigenética. Para probar la importancia de esta observación, recurrimos a los músculos esqueléticos ya que observamos que este tejido expresa niveles más altos de la isoforma macroH2A1.1. Demostramos el cambio de la isoforma que no se une a metabolitos a macroH2A1.1 durante diferenciación miogénica normal. Demostramos que macroH2A1.1 y en parte la integridad de su bolsillo de unión a metabolitos son importantes para la adecuada fusión de mioblastos y maduración de miotúbulos. Demostramos un fenotipo de la capacidad bioenergética y metabólica alterada en las células deficientes en macroH2A1.1 y lo correlacionamos con desregulación de expresión de los genes. Estos genes incluyen genes codificantes de la cadena pesada de la miosina, proteinas marcadores de fibras musculares que difieren en su función metabólica. Correspondientemente, observamos un cambio en la composición del tipo de fibra de los músculos esqueléticos en ratones adultos deficientes en macroH2A1. Por lo tanto, sugerimos que macroH2A1.1 es uno de los factores epigenéticos que definen la respuesta metabólica de los músculos relevantes para la salud de todo el cuerpo y la homeostasis metabólica. Nos atrevemos a especular que las alteraciones de músculos esqueléticos en ratones deficientes en macroH2A1 podrían contribuir a su fenotipo prediabético.Programa de doctorat en BiomedicinaUniversitat Pompeu FabraBuschbeck, MarcusUniversitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut201520152014info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion191 p.application/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/10803/316789TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/3167892026-06-14T12:46:07Z
score 15,301603

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