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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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/316789 |
| Acceso en línea: | http://hdl.handle.net/10803/316789 |
| Access Level: | acceso abierto |
| Palabra clave: | 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 |
| Sumario: | 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. |
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