Muscle stem cells (MuSCs) are essential for the growth, maintenance and regenerative capability of skeletal muscle. These cells, on one side can be activated and become competent for the differentiation, on the other hand they can undergo self-renewal, to guarantee the persistence of the stem cell pool. After birth, MuSCs ensure the maturation of post-natal muscle fibers, generating a high number of mononuclear cells, able to fuse with the growing myofibers. During adulthood, MuSCs are generally quiescent but can be activated upon muscle damage to ensure tissue repair. Epigenetic mechanisms, responsible of time- and space-specific control of gene expression, are involved in the regulation of MuSCs fate and identity. However, how these mechanisms are modulated in MuSCs during the first stages of mouse’s life is only partially understood. In this study, we aimed to identify possible changes in histone modifications in murine MuSCs, focalizing on the repressive histone mark H3K9me3, during the transition from post-natal to adult age. We found that both the levels and the distribution of H3K9me3 mark change in adulthood compared to post-natal age. Integrating these results with analyses of transcriptomes, we also showed that post-natal MuSCs exhibit active transcription of cell cycle genes, while adulthood MuSCs show quiescent-state signature. All together these results suggest that H3K9me3 distribution reflects a different cell state and underline the importance of epigenetic regulation in MuSCs fate. Finally, we reported the case of Cdkn1c, an important gene for the cell cycle dynamics during muscle differentiation, that we found down-regulated during the transition from post-natal to adult stage, due to a remodeling of H3K9me3 domain and chromatin accessibility state.
Le cellule staminali muscolari (MuSCs) sono essenziali per la crescita, mantenimento e capacità rigenerativa del muscolo scheletrico. Queste cellule, da un lato, possono attivarsi e andare incontro a differenziamento; dall’altro, possono auto-rinnovarsi, per garantire l’esistenza del pool di cellule staminali. Dopo la nascita, le MuSCs assicurano la maturazione delle fibre muscolari post-natali, generando un alto numero di cellule mononucleate, in grado di fondersi con le miofibre in crescita. Durante la vita adulta, le MuSCs sono generalmente quiescenti ma possono attivarsi in risposta al danno muscolare. I meccanismi epigenetici, responsabili del controllo dell’espressione genica tempo- e spazio- specifico, sono coinvolti nella regolazione del destino e dell’identità delle MuSCs. Tuttavia, come questi meccanismi siano modulati nelle MuSCs durante i primi stadi della vita del topo è solo parzialmente compreso. Lo scopo di questo lavoro è stato identificare possibili cambiamenti nelle modificazioni istoniche nelle MuSCs murine, focalizzandosi sul marchio istonico repressivo H3K9me3, durante la transizione dalla vita post-natale ad adulta. Abbiamo trovato un cambiamento sia dei livelli che della distribuzione di H3K9me3 nell’età adulta rispetto a quella post-natale. Integrando questi risultati con analisi del trascrittoma, abbiamo mostrato che le MuSCs post-natali trascrivono ad alti livelli i geni coinvolti nel ciclo cellulare, i quali risultano invece trascritti a bassi livelli nell’età adulta. Infine, abbiamo riportato il caso di Cdkn1c, un gene importante per il controllo del ciclo cellulare durante il differenziamento muscolare, il quale risulta down-regolato durante la transizione dalla vita post-natale ad adulta, a causa di un rimodellamento della distribuzione di H3K9me3 e dello stato di accessibilità della cromatina.
Riorganizzazione epigenetica nelle cellule staminali muscolari durante la crescita post-natale del topo
RESCIGNO, ROSA
2020/2021
Abstract
Muscle stem cells (MuSCs) are essential for the growth, maintenance and regenerative capability of skeletal muscle. These cells, on one side can be activated and become competent for the differentiation, on the other hand they can undergo self-renewal, to guarantee the persistence of the stem cell pool. After birth, MuSCs ensure the maturation of post-natal muscle fibers, generating a high number of mononuclear cells, able to fuse with the growing myofibers. During adulthood, MuSCs are generally quiescent but can be activated upon muscle damage to ensure tissue repair. Epigenetic mechanisms, responsible of time- and space-specific control of gene expression, are involved in the regulation of MuSCs fate and identity. However, how these mechanisms are modulated in MuSCs during the first stages of mouse’s life is only partially understood. In this study, we aimed to identify possible changes in histone modifications in murine MuSCs, focalizing on the repressive histone mark H3K9me3, during the transition from post-natal to adult age. We found that both the levels and the distribution of H3K9me3 mark change in adulthood compared to post-natal age. Integrating these results with analyses of transcriptomes, we also showed that post-natal MuSCs exhibit active transcription of cell cycle genes, while adulthood MuSCs show quiescent-state signature. All together these results suggest that H3K9me3 distribution reflects a different cell state and underline the importance of epigenetic regulation in MuSCs fate. Finally, we reported the case of Cdkn1c, an important gene for the cell cycle dynamics during muscle differentiation, that we found down-regulated during the transition from post-natal to adult stage, due to a remodeling of H3K9me3 domain and chromatin accessibility state.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/13894