MEF2C/p300-mediated epigenetic remodeling promotes the maturation of induced cardiomyocytes.
Stem Cell Reports
; 18(6): 1274-1283, 2023 06 13.
Article
em En
| MEDLINE
| ID: mdl-37315521
ABSTRACT
Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Miócitos Cardíacos
/
Montagem e Desmontagem da Cromatina
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Fatores de Transcrição de p300-CBP
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Fatores de Transcrição MEF2
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Stem Cell Reports
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Japão