Dataset Information


NCoR/SMRT co-repressors cooperate with c-MYC to create an epigenetic barrier to somatic cell reprogramming [ChIP-Seq]

ABSTRACT: Changing the somatic cell transcriptome to a pluripotent state using exogenous reprogramming factors needs transcriptional co-regulators that help activate or suppress gene expression and rewrite the epigenome. Here, we show that reprogramming-specific engagement of the NCoR/SMRT co-repressor complex at key pluripotency loci creates an epigenetic block to reprogramming. HDAC3 executes the repressive function of NCoR/SMRT in reprogramming by inducing histone deacetylation at these loci. Recruitment of NCoR/SMRT-HDAC3 to pluripotency genes is facilitated by all 4 Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) but mostly by c-MYC. Class IIa HDACs further potentiate this recruitment by interacting with both the reprogramming factors and NCoR/SMRT. Consequently, depleting NCoR/SMRT-HDAC3 function enables high efficiency of reprogramming, while elevating NCoR/SMRT-HDAC3 recruitment at pluripotency loci by over-expressing constitutively active class IIa HDACs derails it. Our findings thus uncover an unexpected epigenetic mechanism involving c-MYC, whose manipulation greatly enhances reprogramming efficiency. Overall design: ChIP-seq data consisting of NCoR or SMRT binding in ESCs, OSKM-transfected MEFs (Day 9) and H3K27ac ChIP-seq in OSKM-transfected MEFs (Day 5, 9 and 13) either co-transfected with a FLAG control or a HDAC3-Y298F deacetylase null mutant

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Andrew Paul Hutchins  

PROVIDER: GSE70736 | GEO | 2018-03-07


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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 ki  ...[more]

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