Abstract
Somatic cell reprogramming by exogenous factors requires cooperation with transcriptional co-activators and co-repressors to effectively remodel the epigenetic environment. How this interplay is regulated remains poorly understood. Here, we demonstrate that NCoR/SMRT co-repressors bind to pluripotency loci to create a barrier to reprogramming with the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC), and consequently, suppressing NCoR/SMRT significantly enhances reprogramming efficiency and kinetics. The core epigenetic subunit of the NCoR/SMRT complex, histone deacetylase 3 (HDAC3), contributes to the effects of NCoR/SMRT by inducing histone deacetylation at pluripotency loci. Among the Yamanaka factors, recruitment of NCoR/SMRT-HDAC3 to genomic loci is mostly facilitated by c-MYC. Hence, we describe how c-MYC is beneficial for the early phase of reprogramming but deleterious later. Overall, we uncover a role for NCoR/SMRT co-repressors in reprogramming and propose a dual function for c-MYC in this process.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Cellular Reprogramming*
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Epigenesis, Genetic*
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Gene Expression Regulation, Developmental
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HEK293 Cells
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Histones / metabolism
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Humans
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Inbred ICR
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Mouse Embryonic Stem Cells / metabolism*
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Nuclear Receptor Co-Repressor 1 / genetics
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Nuclear Receptor Co-Repressor 1 / metabolism*
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Nuclear Receptor Co-Repressor 2 / genetics
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Nuclear Receptor Co-Repressor 2 / metabolism*
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Pluripotent Stem Cells / metabolism*
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Signal Transduction
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Time Factors
Substances
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Histones
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KLF4 protein, human
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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Ncor1 protein, mouse
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Ncor2 protein, mouse
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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Octamer Transcription Factor-3
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Proto-Oncogene Proteins c-myc
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SOXB1 Transcription Factors
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Histone Deacetylases
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histone deacetylase 3